Metabolically inert antifolates for treating disorders of abnormal cellular proliferation and inflammation

ABSTRACT

The present invention provides compositions and methods for the treatment of disorders of abnormal cell proliferation and/or inflammation, such as psoriasis and inflammatory bowel disease, in a human or other host animals.

The present application is a continuation of U.S. patent applicationSer. No. 11/223,433, filed Sep. 8, 2005, which claims priority to U.S.Prov. App. No. 60/607,883, filed Sep. 8, 2004, and U.S. Prov. App. No.60/611,482, filed Sep. 20, 2004, the disclosures of which areincorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The invention is in the area of pharmaceutical chemistry, and is inparticular, metabolically inert etiolate compounds for the preventionand treatment of disorders of abnormal cell proliferation and/orinflammation, such as psoriasis and Crohn's disease.

BACKGROUND OF THE INVENTION

Disorders of abnormal cell proliferation are characterized byinappropriate growth or multiplication of one or more cell types. Theyinclude malignant (i.e., cancer) as well as non-malignant disorders.Many of these diseases also include an inflammatory component. Psoriasisrepresents one type of non-malignant disorder of abnormal cellproliferation. The disorder is characterized by psoriatic skin plaquesrepresenting highly localized sites of deregulated growth andinflammation. While the cause of psoriasis is poorly understood, it isthought to involve both a genetic and environmental component.Moderate-to-severe psoriasis has traditionally been treated withsystemic therapies such as cyclosporine, methotrexate, retinoids, andphototherapy (i.e., ultraviolet B, psoralen plus ultraviolet A).Traditional treatments, however, suffer limitations includingsignificant side effects, lack of durable efficacy, and inconvenientadministration schedules.

Uncontrolled or inappropriate chronic inflammatory responses arecharacteristic of a variety of diseases and disorders. Inflammatorybowel disease (IBD), including both Crohn's disease and ulcerativecolitis, provides one example of an inflammatory disorder. IBD affectsthe quality of life of more than one million Americans. At present,aminosalicylates (5-ASA), corticosteroids, immune modifiers andantibiotics are used to treat Crohn's disease. Current therapies,however, are ineffective in many patients and present significant sideeffects including slow onset of action and toxicity.

Antifolates are compounds that interfere with various stages of foliatemetabolism. An intact foliate enzyme pathway is important to maintain denovo synthesis of the building blocks of DNA, as well as of theimportant amino acids. Antifolate targets include the various enzymesinvolved in foliate metabolism, including (i) dihydrofolate reductase(DHFR); (ii) thymidylate synthase (TS); (iii) folylpolyglutamylsynthase; and (iv) glycinamide ribonucleotide (GAR) and aminoimidazolecarboxamide ribonucleotide (AICAR) transformylases.

Antifolates are folate acid analogs. For a general review ofantifolates, see Montgomery J A and Piper Jr. Design and Synthesis ofFolate Analogs as Antimetabolites. In Folate Antagonists as TherapeuticAgents. Volume 1: Biochemistry, Molecular Actions and Synthetic Design.Eds. Sirotnak F M, Burchall J J, Ensminger W D and Montgomery J A.Academic Press. pp 219-261, 1984; Thomas W. Current Oncology Reports(2003) 5:114-125; Graffner N M. Approaches to Soft Drug Analogues ofDihydrofolate Reductase Inhibitors, in Comprehensive Summaries ofUppsala Dissertations from the Faculty of Pharmacy 252 (2001); Beale,P., and Clarke, S. Tomudex. Clinical development. In: A. L. Jackman(ed.), Antifolate Drugs in Cancer Therapy, pp. 167-191. Allegra C J:Antifolates, in Chabner B A, Collins J M (eds): Cancer Chemotherapy:Principles & Practice, pp 110-153. Philadelphia, Lippincott, 1990.

Folic acid contains a pteridine ring, para-aminobenzoic acid and aglutamate residue.

Methotrexate, a DHFR inhibitor, is among the earliest antifolates. It isa classical antifolate, meaning it is characterized by ap-aminobenzogylglutamic acid side chain, and closely resembles the folicacid molecule. MTX differs from folic acid by the substitution of anamino group for a hydroxyl at the 4-position of the pterdine ring and bythe methylation of the amine of the para-aminobenzoic moeity. Thesubstitution of an amino group for a hydroxyl at the 4-position of thepterdine ring changes the enzyme substrate into a tight bindinginhibitor of DHFR.

Both MTX and naturally occurring folate compounds undergo intracellularmetabolism to polyglutamate derivatives. This polyglutamylation iscatalyzed by the enzyme folylpolyglutamyl synthase (FPGS), whichattaches up to six glutamate residues to the molecule, which helps totrap it within the cell. Polyglutamylation of MTX occurs more slowlycompared to naturally occurring antifolates, but the resultingmethotrexate polyglutamylates have extremely long intra cellularhalf-lives, and can be detected in some tissues more than several monthsafter a single drug administration (Takimoto C H et al. Oncology (1995)9(7): 649-656).

The most common use of MTX is as an anti-cancer drug. MTX is curative ofchoriocarcinoma and Burkett's lymphoma. It has also widely used as asingle agent or in combination with other drugs for the treatment ofvarious forms of human cancer. More recently, MTX has been shown to haveanti-inflammatory and immunosuppressive properties with accompanyingactivity against autoimmune disorders. MTX is now widely prescribed asan immunosuppressive agent in the treatment of autoimmune diseases,including rheumatoid arthritis (Weinblatt M E et al. N. Engl. J. Med.(1985) 312:818; Wilke W S (Ed). Methotrexate Therapy in RheumaticDisease. Marcel Dekker, Inc. (1989). Intrinsic and acquired resistanceto MTX and other antifolate analogues limits their clinicaleffectiveness, however. Apart from resistance, major limitations of MTXtreatment include bone marrow toxicity, gastrointestinal ulceration andliver and kidney damage.

A number of antifolates have been designed to overcome theselimitations. Rational design has focused, for example, on thedevelopment of antifolates with greater lipid solubility and/or improvedtransport characteristics relative to methotrexate (Takimoto C H et al.Oncology (1995) 9(7); 649-656). Representative non-classical agentsinclude trimetrexate and piritrexim (Kamen B A et al. J. Biochem.Pharmacol. (1984) 33: 1697-1984; Duch D S et al. Cancer Res. (1982) 42:3987-3994). Unlike classical antifolates, non-classical antifolates lackthe glutamate moiety, and therefore do not require carrier-mediatedcellular uptake. These lipophilic antifolates are used againstopportunistic infections (e.g., Pneumocystic carinii pneumonia, PCP) inindividuals with AIDS and other disorders of the immune system and haveundergone extensive clinical testing as anticancer agents.

Inhibitors of glycinamide ribotide formyltransferase (GARFT) have alsobeen developed. Lometrexol ((5,10-dideazatetrahydrofolate [DDATHF]) is aspecific GARFT inhibitor that has shown anti-tumor properties (Habeck LL et al. Cancer Res. (1994) 54: 1021-1026). Early clinical trials,however, were confounded by cumulative myelosuppression that preventedrepetitive administration (Roberts J D. Cancer Chemother Pharmacol.(2000) 45(2):103-10). LY309887(6R-2′,5′-thienyl-5,10-dideazatetrahydrofolic acid) is a thiopheneanalogue of lometrexol, is a second generation GARFT inhibitor(Mendelsohn L G. Investig. New Drugs (1996) 14: 287-294).

In 1991, Nair et al. demonstrated that contrary to the widely acceptednotion, polyglutamylation of classical antifolates is not essential foranti-tumor activity and further, that this metabolic transformation isactually undesirable because it may cause the loss of pharmacologicalcontrol and target specificity of the drug (Nair M G et al.

Other antifolates in clinical development specifically targetfolate-dependent enzymes such as TS or GARFT, thereby directly affectingpools of nucleotides available for DNA synthesis (Takemura Y. et al.Anti-Cancer Drugs (1997) 8: 3-16; Habeck L L et al. Cancer Res (1994)54: 1021-1026). Direct and specific TS inhibitors have been studied aspotential anticancer drugs (Stout T J et al. Biochemistry (1999) 38:1607-1617). Of these, Tomudex (raltitrexed; ZD1649),[N-{5-[N-(3-,4-dihydro-2-methyl-4-oxoquinazoline-6-yl-methyl)-N-methylamine]-2-theroyl}-L-gluteiacid], is one of the most extensively evaluated and has been approvedfor treatment in Europe (Van Custom Euro. J. Cancer, (1999) 35(Suppl.1):1-2; Jack man AL. Invest. New Drugs, (1996) 14: 305-316). Comdexundergoes substantial polyglutamylation within the cell. Comdex and itspolyglutamates do not appear to inhibit DHFR, GAR or AICARtransformylase, suggesting that the drug is a pure TS inhibitor.

J. Med. Chem (1991) 34: 222-227). This new finding let to the discoveryof a number of nonpolyglutamylatable classical antifolates (Nair M G etal. Proc. Amer. Assoc. Cancer. Research. (1998) 39:431).

U.S. Pat. No. 5,073,554 (Nair) describes methylene-1-deazaaminopterine(MDAM), a nonpolyglutamylatable antifolate compound. MDAM has beendeveloped as an experimental anticancer drug for the treatment of humansolid tumors (Cao S. et al. Clinical Cancer Research (1996) 2(4):707-712); Johansen M et al. Cancer Chemother Pharmacol. (2004)53(5):370-6). U.S. Pat. No. 5,550,128 (Nair et al) describes the activeenantiomer of MDAM as the one possessing the L-configuration.

Further investigation by Nair et al. of the metabolic disposition ofcertain non-polyglutamylatable antifolates led to the unexpected findingthat the presence of the 4-methyleneglutamate moiety modulates thebinding of such compounds to the liver enzyme aldehyde oxidase, whichmediates their oxidative deactivation to the corresponding 7-hydroxyderivatives (Cellular. Pharmacology (1996) 3: 29). U.S. Pat. No.5,912,251 (Nair) describes metabolically inert classical antifolates,including 4-Amino-4-deoxy-5,8,10-trideazapteroyl-4′-methylene glutamicacid, which are non-polyglutamylatable and non-hydroxylatable. They aresaid to be useful in the treatment of neoplastic disease (leukemia,ascetic and solid tumors), asthma and related anti-inflammatory disease,and for the treatment of rheumatoid arthritis and other autoimmunediseases.

wherein X is CH₂, CHCH₃, CH(CH₂CH₃), NH, or NCH₃.

wherein X is CH₂.

MTREX

U.S. Pat. No 5,912,251 to Nair discloses certain antifolate compoundsfor the treatment of neoplastic diseases, asthma, and/or rheumatoidarthritis.

There remains a strong need to provide effective agents to treatdiseases and disorders of abnormal cell proliferation and/orinflammation.

It is therefore an object of the present invention to providecompositions and methods for the treatment of diseases and disorderscharacterized by abnormal cell proliferation, such as psoriasis.

It is a further object of the present invention to provide compositionsand methods for the treatment of diseases and disorders characterized byinflammation, including inflammatory bowel disease.

SUMMARY OF THE INVENTION

The present invention provides metabolically inert antifolate compounds,or pharmaceutically acceptable formulations containing these compounds,for use in the prevention and treatment of disorders characterized byabnormal cell proliferation and/or inflammation, such as psoriasis andCrohn's disease.

A method for the treatment of disorders characterized by abnormal cellproliferation and/or inflammation is also disclosed that includesadministering an effective amount of the metabolically inert antifolatecompound of the present invention, administered alone or in combinationwith another anti-proliferation or anti-inflammation agent, optionallyin a pharmaceutically acceptable carrier.

In one embodiment, the compound of Formula (I) is provided as well as amethod for the treatment of a host with a disease or disordercharacterized by non-neoplastic abnormal cell proliferation,non-asthmatic inflammation including, but not limited to, inflammatorybowel disease (e.g., Crohn's disease) and/or chronic obstructivepulmonary disease (COPD), and/or non-rheumatoid arthritic auto-immunedisease including, but not limited to, psoriasis, osteoarthritis, and/ormultiple sclerosis (MS), comprising administering an effective treatmentamount of compound of Formula (I):

or its pharmaceutically acceptable salt, ester, salt of an ester, amide,salt or an amide, prodrug, salt of a prodrug, or a steroisomeric,tautomeric or polymorphic form thereof; wherein

-   X is CH₂, CHCH₃, CH(CH₂CH₃), NH, NCH₃, or NR⁷-   R¹, R², R³, R⁴, and R⁷ are independently selected from H, optionally    substituted alkyl including lower alkyl, optionally substituted    alkenyl or alkynyl, acyl, —C(O)-(alkyl), —C(O)(lower alkyl),    —C(O)-(alkenyl), —C(O)-(alkynyl), —C(═Y³)V³, lipid, phospholipid,    carbohydrate, peptide, cholesterol, an amino acid residue or    derivative, an amino acid acyl residue or derivative or other    pharmaceutically acceptable leaving group that is capable of    providing a free amine when administered in vivo;-   R⁵ and R⁶ are independently selected from H, optionally substituted    alkyl including lower alkyl, optionally substituted alkenyl or    alkynyl, lipid, phospholipid, carbohydrate, peptide, cholesterol, an    amino acid residue or derivative, or other pharmaceutically    acceptable leaving group that is capable of providing a —C(═Y)V⁻ or    —C(═Y)VH moiety when administered in vivo;-   each Y¹, Y², and Y³ independently is O, S or NJ¹;-   each V¹ and V² independently is O, S or NJ¹-   each V³ independently is OH, OJ¹, SH, SJ¹, NH₂, NHJ¹, NJ¹J², CH₃,    CH₂R¹⁰¹, CHR¹⁰¹R¹⁰², CR¹⁰¹ _(R) ¹⁰²R¹⁰³;-   each J¹, J² and J³ independently are hydrogen, alkyl, alkenyl,    alkynyl, alkaryl, cycloalkyl, aryl, cycloaryl, heteroalkyl,    heterocycle, heteroaryl, hydroxyl, alkoxy, or amine; and-   each R¹⁰⁰, R¹⁰¹, R¹⁰²; and R¹⁰³ are independently hydrogen, alkyl,    alkenyl, alkynyl, aryl, acyl, heteroaromatic, heteroaryl,    heteroalkyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro, SO₂,    SO₃, thioalkyl, or amino.

In one embodiment of the present invention, a method for the treatmentof a host with a disease or disorder characterized by non-neoplasticabnormal cell proliferation is provided. Diseases or disorderscharacterized by non-neoplastic abnormal cell proliferation include, butare not limited to, (i) skin disorders including, without limitation,psoriasis (all types), eczema, acne, acne vulgaris, acne inverse,rosacea, common warts, anogenital (venereal) warts, lupus associatedskin lesions, dermatitides (e.g., such as atopic dermatitis, contactdermatitis, seborrheic dermatitis and solar dermatitis), keratoses(e.g., seborrheic keratosis, keratosis follicularis, senile keratosis,actinic keratosis, photo-induced keratosis), skin ageing (e.g.,photo-induced skin aging), keloids, eukoplakia, lichen planus,keratitis, urticaria, pruritus, hidradenitis, pemphigus vulgaris; (ii)bowel disorders; (iii) blood vessel disorders including, withoutlimitation, ischemic-reperfusion related brain edema and injury,cortical ischemia, ovarian hyperplasia and hypervascularity, (polycysticovary syndrome), endometriosis, psoriasis, diabetic retinopathy, andother ocular angiogenic diseases such as retinopathy of prematurity(retrolental fibroplastic), macular degeneration, corneal graftrejection, neuroscular glaucoma and Oster Webber syndrome; (iv)cardiovascular disorders including, for example, hypertension,vasculo-occlusive diseases (e.g., atherosclerosis, thrombosis andrestenosis after angioplasty), acute coronary syndromes (e.g., unstableangina, myocardial infarction, ischemic and non-ischemiccardiomyopathies, post-MI cardiomyopathy and myocardial fibrosis, andsubstance-induced cardiomyopathy), ischemic heart disease; (v) fibroticdisorders including, without limitation, fibrosis and other medicalcomplications of fibrosis which result in whole or in part from theproliferation of fibroblasts, and hepatic cirrhosis; (vi) mesangialdisorders including, without limitation, human renal diseases such asglomerulonephritis, diabetic nephropathy, malignant nephrosclerosis,thrombotic microangiopathy syndromes, transplant rejection, andglomerulopathies; (vii) graft-versus-host rejection; (viii) urogenitaldisorders including, without limitation, endometriosis, benign prostatichyperplasia, eiomyoma, polycystic kidney disease, and diabeticnephropathy; (ix) disorders of the tissue and joints including, withoutlimitation Raynaud's phenomenon/disease, Sjogren's Syndrome systemicsclerosis, systemic lupus erythematosus, vasculitides, ankylosingspondylitis, osteoarthritis, reactive arthritis, psoriatic arthritis,fibromyalgia; (x) degenerative neurological disorders such asParkinson's disease and Alzheimer's disease; (xi) virus-inducedhyperproliferative diseases including, for example, human papillomavirus-induced disease (e.g., lesions caused by human papilloma virusinfection), Epstein-Barr virus-induced disease, acquired immunedeficiency syndrome (AIDS)-induced disease, scar formation, genitalwarts, cutaneous warts, and the like; (xii) pulmonary disordersincluding, without limitation, chronic obstructive pulmonary disease(COPD), reactive airway disease, pulmonary fibrosis, acute respiratorydistress syndrome (ARDS) pulmonary hypertension; (xiii) other diseasesand disorders including Behcet's syndrome, Fibrocystic breast disease,fibroadenoma, chronic fatigue syndrome, post-dialysis syndrome,vasculitis, lipid histiocytosis, septic shock, and familial intestinalpolyposes such as Gardner syndrome. The compound of Formula (I) can beadministered either alone or in combination with one or more otheranti-proliferative agent, optionally in a pharmaceutically acceptablecarrier to treat a disease or disorder characterized by non-neoplasticabnormal cell proliferation.

In another embodiment of the present invention, a method for thetreatment of a host with a disease or disorder characterized bynon-asthmatic inflammation is provided. Disorders characterized bynon-asthmatic inflammatory diseases associated with abnormal cellproliferation include, but are not limited to, inflammatory boweldisease (IBD) (e.g., Crohn's disease (CD) and ulcerative colitis (UC)),chronic obstructive pulmonary disease (COD), sarcidosis, non-rheumatoidarthritis (e.g., fibromyalgia, fibrositis, myofascil pain, humeralepicondyltitis, frozen shoulder, Tietze's syndrome, fascitis,tendonitis, tenosynovitis, bursitis, juvenile chronic arthristis,spondyloarthropaties, hyperuricemia, and arthristis associated withacute gout, chronic gout and systemic lupus erthematosus,osteoarthristis), multiple sclerosis (MS), proliferativeglomerulonephritis, lupus erythematosus, scleroderma, temporalarteritis, thromboangiitis obliterans, mucocutaneous lymph nodesyndrome, host versus graft, thyroiditis, Grave's disease,antigen-induced airway hyperactivity, pulmonary eosinophilia,Guillain-Barre syndrome, allergic rhinitis, myasthenia gravis, humanT-lymphotrophic virus type 1-associated myelopathy, herpes simplexencephalitis, inflammatory myopathies, Goodpasture's syndrome,poststreptococcal and autoimmune renal failure, septic shock, systemicinflammatory response syndrome (SIRS), adult respiratory distresssyndrome (ARDS), envenomation, Hashimoto's thyroiditis, autoimmunehemolytic anemias, insulin dependent diabetes mellitus, rheumatic fever,pelvic inflammatory disease (PID), conjunctivitis, dermatitis,bronchitis, rhinitis, and cardiovascular diseases, including restenosis,atherosclerosis, atherosclerotic complications resulting from plaquerupture, severe tissue ischemia, and heart failure. The compound ofFormula (I) can be administered either alone or in combination with oneor more other anti-proliferative agent, optionally in a pharmaceuticallyacceptable carrier to treat a non-asthmatic inflammation disorder.

In one embodiment, a method for the treatment of psoriasis in a host,including a human, is disclosed that involves administering an effectiveamount of the compound of Formula (I), administered either alone or incombination with one or more other anti-psoriasis agents, optionally ina pharmaceutically acceptable carrier.

In another embodiment, a method for the treatment of inflammatory boweldisease in a host, including a human, is disclosed that involvesadministering an effective amount of the compound of Formula (I),administered either alone or in combination with one or more otheranti-inflammatory bowel disease agents, optionally in a pharmaceuticallyacceptable carrier. In one embodiment, the inflammatory bowel disease isCrohn's disease. In another embodiment, the inflammatory bowel diseaseis ulcerative colitis.

In another embodiment, a method for the treatment of osteoarthritis in ahost, including a human, is disclosed that involves administering aneffective amount of the compound of Formula (I), administered eitheralone or in combination with one or more other anti-osteoarthritisagents, optionally in a pharmaceutically acceptable carrier.

In yet another embodiment, a method for the treatment of chronicobstructive pulmonary disease (COPD) in a host, including a human, isdisclosed that involves administering an effective amount of thecompound of Formula (I), administered either alone or in combinationwith one or more other anti-COPD agents, optionally in apharmaceutically acceptable carrier.

In another preferred embodiment, a method for the treatment of multiplesclerosis (MS) in a host, including a human, is disclosed that involvesadministering an effective amount of the compound of Formula (I),administered either alone or in combination with one or more otheranti-MS agent, optionally in a pharmaceutically acceptable carrier.

In an alternative embodiment, the compound of Formula (II) is providedas well as a method for the treatment of a host with a disordercharacterized by abnormal cell proliferation, inflammation, and/orauto-immune disease, comprising administering an effective treatmentamount of a compound of Formula (II):

or its pharmaceutically acceptable salt, ester, salt of an ester, amide,salt or an amide, prodrug, salt of a prodrug, or a steroisomeric,tautomeric or polymorphic form thereof; wherein

-   X is CH₂, CHCH₃, CH(CH₂CH₃), NH, NCH₃, or NR⁷-   R¹, R², R³, R⁴, and R⁷ are independently selected from H, optionally    substituted alkyl including lower alkyl, optionally substituted    alkenyl or alkynyl, acyl, —C(O)-(alkyl), —C(O)(lower alkyl),    —C(O)-(alkenyl), —C(O)-(alkynyl), —C(═Y³)V³, lipid, phospholipid,    carbohydrate, peptide, cholesterol, an amino acid residue or    derivative, an amino acid acyl residue or derivative or other    pharmaceutically acceptable leaving group that is capable of    providing a free amine when administered in vivo;-   R⁵ and R⁶ are independently selected from H, optionally substituted    alkyl including lower alkyl, optionally substituted alkenyl or    alkynyl, lipid, phospholipid, carbohydrate, peptide, cholesterol, an    amino acid residue or derivative, or other pharmaceutically    acceptable leaving group that is capable of providing a —C(═Y)V⁻ or    —C(═Y)VH moiety when administered in vivo;-   each Y¹, Y², and Y³ independently is O, S or NJ¹;-   each V¹ and V² independently is O, S or NJ¹-   each V³ independently is OH, OJ¹, SH, SJ¹, NH₂, NHJ¹, NJ¹J², CH₃,    CH₂R¹⁰¹, CHR¹⁰¹R¹⁰², or CR¹⁰¹R¹⁰²R¹⁰³;-   each J¹, J² and J³ independently are hydrogen, alkyl, alkenyl,    alkynyl, alkaryl, cycloalkyl, aryl, cycloaryl, heteroalkyl,    heterocycle, heteroaryl, hydroxyl, alkoxy, or amine; and-   each R¹⁰⁰, R¹⁰¹, R¹⁰², and R¹⁰³ are independently hydrogen, alkyl,    alkenyl, alkynyl, aryl, acyl, heteroaromatic, heteroaryl,    heteroalkyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro, SO₂,    SO₃, thioalkyl, or amino;-   such that, if Y¹ and Y² are both oxygen, and V¹ and V² are both    oxygen, then at least one of R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ is not    H.

In one embodiment, a method for the treatment of abnormal cellproliferation in a host, including a human, is disclosed that involvesadministering an effective amount of the compound of Formula (II),administered either alone or in combination with one or more otheranti-abnormal cell proliferation agents, optionally in apharmaceutically acceptable carrier.

In one embodiment, a method for the treatment of an autoimmune disorderin a host, including a human, is disclosed that involves administeringan effective amount of the compound of Formula (II), administered eitheralone or in combination with one or more other agents effective in thetreatment of an autoimmune disorder.

In another embodiment, a method for the treatment of an inflammatorydisease in a host, including a human, is disclosed that involvesadministering an effective amount of a of the compound of Formula (II),administered either alone or in combination with one or more otheranti-inflammatory agents, optionally in a pharmaceutically acceptablecarrier, optionally in a pharmaceutically acceptable carrier.

In another embodiment, a method for the treatment of psoriasis in ahost, including a human, is disclosed that involves administering aneffective amount of the compound of Formula (II), administered eitheralone or in combination with one or more other anti-psoriasis agents,optionally in a pharmaceutically acceptable carrier.

In another embodiment, a method for the treatment of inflammatory boweldisease in a host, including a human, is disclosed that involvesadministering an effective amount of the compound of Formula (II),administered either alone or in combination with one or more otheranti-inflammatory bowel disease agents, optionally in a pharmaceuticallyacceptable carrier. In one embodiment, the inflammatory bowel disease isCrohn's disease. In another embodiment, the inflammatory bowel diseaseis ulcerative colitis.

In another embodiment, a method for the treatment of osteoarthritis in ahost, including a human, is disclosed that involves administering aneffective amount of the compound of Formula (II), administered eitheralone or in combination with one or more other anti-osteoarthritisagents, optionally in a pharmaceutically acceptable carrier.

In yet another embodiment, a method for the treatment of chronicobstructive pulmonary disease (COPD) in a host, including a human, isdisclosed that involves administering an effective amount of thecompound of Formula (II), administered either alone or in combinationwith one or more other anti-COPD agents, optionally in apharmaceutically acceptable carrier.

In another embodiment, a method for the treatment of multiple sclerosis(MS) in a host, including a human, is disclosed that involvesadministering an effective amount of the compound of Formula (II),administered either alone or in combination with one or more otheranti-MS agents, optionally in a pharmaceutically acceptable carrier.

The compounds of the present invention can be administered, for example,by parenteral, intraperitoneal, intravenous, intradermal, epidural,intraspinal, infrasternal, intra-articular, intra-synovial, intrathecal,intra-arterial, intracardiac, intramuscular, intranasal, subcutaneous,intraorbital, intracapsular, topical, transdermal patch, via rectal,vaginal or urethral administration including via suppository,percutaneous, nasal spray, surgical implant, internal surgical paint,infusion pump administration or via catheter, stent, balloon or otherdelivery device. In one embodiment, the agent and carrier can beadministered in a controlled release formulation such as a monolithicmatrix device. In another embodiment, the compounds and compositionsdescribed herein can be administered as microcrystalline cellulosetablets. In one particular embodiment, the compounds and compositionsdescribed herein can be administered intravenously. In one particularembodiment of the present invention, the compounds and/or compositionsdescribed herein can be administered topically. In one embodiment, thecompounds and compositions can be administered topically to treat anabnormal cell proliferation disorder, for example, psoriasis. In anotherparticular embodiment, the compounds and/or compositions describedherein can be administered topically, for example, as a cream, for thetreatment of psoriasis.

DESCRIPTION OF THE FIGURES

FIG. 1 provides an illustration of the metabolically inertcharacteristics of the compound of Formula I, as described furtherbelow.

FIG. 2 provides an illustration of the synthesis of a sub-embodiment ofthe compound of Formula I, as described further below.

DETAILED DESCRIPTION OF THE INVENTION

Disclosed herein is a compound, method and composition for the treatmentof abnormal cell proliferation and/or inflammation in a human and otherhost animals. The method includes administration of an effectiveanti-proliferative or anti-inflammatory amount of the compoundsdescribed herein. The compounds of this invention either possesanti-proliferative and/or anti-inflammatory activity, or are metabolizedto a compound that exhibits such activity. In one embodiment of thepresent invention, the composition and method are used to treatpsoriasis. In an alternative embodiment, the composition and method areused to treat inflammatory bowel disease, such as Crohn's disease.

I. Compounds

The compositions of the present invention are metabolically inertantifolates. The term “metabolically inert antifolate” is intended toinclude compounds that are (i) folic acid analogs capable of disruptingfolate metabolism; (ii) non-polyglutamylatable; and (iii)non-hydroxylatable. A representation of the metabolically inertcharacteristics of the compounds of the present invention, asillustrated for a particular sub embodiment, is provided in FIG. 1.

Antifolates are compounds that interfere with various stages of foliatemetabolism. An intact foliate enzyme pathway is important to maintain denovo synthesis of the building blocks of DNA, as well as of theimportant amino acids. Antifolate targets include the various enzymesinvolved in foliate metabolism, including (i) dihydrofolate reductase(DHFR); thymidylate synthase (TS); (iii) folylpolyglutamyl synthase; and(iv) glycinamide ribonucleotide (GAR) and aminoimidazole carboxamideribonucleotide (AICAR) transformylases.

Antifolates are folate acid analogs. For a general review ofantifolates, see Montgomery J A and Piper Jr. Design and Synthesis ofFolate Analogs as Antimetabolites. In Folate Antagonists as TherapeuticAgents. Volume 1: Biochemistry, Molecular Actions and Synthetic Design.Eds. Sirotnak F M, Burchall J J, Ensminger W D and Montgomery J A.Academic Press. pp 219-261, 1984; Thomas W. Current Oncology Reports(2003) 5:114-125; Graffner N M. Approaches to Soft Drug Analogues ofDihydrofolate Reductase Inhibitors, in Comprehensive Summaries ofUppsala Dissertations from the Faculty of Pharmacy 252 (2001); Beale,P., and Clarke, S. Tomudex. Clinical development. In: A. L. Jackman(ed.), Antifolate Drugs in Cancer Therapy, pp. 167-191. Allegra C J:Antifolates, in Chabner B A, Collins J M (eds): Cancer Chemotherapy:Principles & Practice, pp 110-153. Philadelphia, Lippincott, 1990.

Folic acid contains a pteridine ring, para-aminobenzoic acid and aglutamate residue.

Methotrexate, a DHFR inhibitor, is among the earliest antifolates. It isa classical antifolate, meaning it is characterized by ap-aminobenzogylglutamic acid side chain, and closely resembles the folicacid molecule. MTX differs from folic acid by the substitution of anamino group for a hydroxyl at the 4-position of the pterdine ring and bythe methylation of the amine of the para-aminobenzoic moeity. Thesubstitution of an amino group for a hydroxyl at the 4-position of thepterdine ring changes the enzyme substrate into a tight bindinginhibitor of DHFR.

Both MTX and naturally occurring folate compounds undergo intracellularmetabolism to polyglutamate derivatives. This polyglutamylation iscatalyzed by the enzyme folylpolyglutamyl synthase (FPGS), whichattaches up to six glutamate residues to the molecule, which helps totrap it within the cell. Polyglutamylation of MTX occurs more slowlycompared to naturally occurring antifolates, but the resultingmethotrexate polyglutamylates have extremely long intracellularhalf-lives, and can be detected in some tissues more than several monthsafter a single drug administration (Takimoto C H et al. Oncology (1995)9(7): 649-656).

The most common use of MTX is as an anti-cancer drug. MTX is curative ofchoriocarcinoma and Burkett's lymphoma. It has also widely used as asingle agent or in combination with other drugs for the treatment ofvarious forms of human cancer. More recently, MTX has been shown to haveanti-inflammatory and immunosuppressive properties with accompanyingactivity against autoimmune disorders. MTX is now widely prescribed asan immunosuppressive agent in the treatment of autoimmune diseases,including rheumatoid arthritis (Weinblatt M E et al. N. Engl. J. Med.(1985) 312:818; Wilke W S (Ed). Methotrexate Therapy in RheumaticDisease. Marcel Dekker, Inc. (1989). Intrinsic and acquired resistanceto MTX and other antifolate analogues limits their clinicaleffectiveness, however. Apart from resistance, major limitations of MTXtreatment include bone marrow toxicity, gastrointestinal ulceration andliver and kidney damage.

A number of antifolates have been designed to overcome theselimitations. Rational design has focused, for example, on thedevelopment of antifolates with greater lipid solubility and/or improvedtransport characteristics relative to methotrexate (Takimoto C H et al.Oncology (1995) 9(7); 649-656). Representative non-classical agentsinclude trimetrexate and piritrexim (Kamen B A et al. J. Biochem.Pharmacol. (1984) 33: 1697-1984; Duch D S et al. Cancer Res. (1982) 42:3987-3994). Unlike classical antifolates, non-classical antifolates lackthe glutamate moiety, and therefore do not require carrier-mediatedcellular uptake. These lipophilic antifolates are used againstopportunistic infections (e.g., Pneumocystic carinii pneumonia, PCP) inindividuals with AIDS and other disorders of the immune system and haveundergone extensive clinical testing as anticancer agents.

Other antifolates in clinical development specifically targetfolate-dependent enzymes such as TS or GARFT, thereby directly affectingpools of nucleotides available for DNA synthesis (Takemura Y. et al.Anti-Cancer Drugs (1997) 8: 3-16; Habeck L L et al. Cancer Res (1994)54: 1021-1026). Direct and specific TS inhibitors have been studied aspotential anticancer drugs (Stout T J et al. Biochemistry (1999) 38:1607-1617). Of these, Tomudex (raltitrexed; ZD1649),[N-{5-[N-(3-,4-dihydro-2-methyl-4-oxoquinazoline-6-yl-methyl)-N-methylamine]-2-theroyl}-L-gluteiacid], is one of the most extensively evaluated and has been approvedfor treatment in Europe (Van Custom Euro. J. Cancer, (1999) 35(Suppl.1):1-2; Jack man AL. Invest. New Drugs, (1996) 14: 305-316). Comdexundergoes substantial polyglutamylation within the cell. Comdex and itspolyglutamates do not appear to inhibit DHFR, GAR or AICARtransformylase, suggesting that the drug is a pure TS inhibitor.

Inhibitors of glycinamide ribotide formyltransferase (GARFT) have alsobeen developed. Lometrexol ((5,10-dideazatetrahydrofolate [DDATHF]) is aspecific GARFT inhibitor that has shown anti-tumor properties (Habeck LL et al. Cancer Res. (1994) 54: 1021-1026). Early clinical trials,however, were confounded by cumulative myelosuppression that preventedrepetitive administration (Roberts J D. Cancer Chemother Pharmacol.(2000) 45(2):103-10). LY309887(6R-2′,5′-thienyl-5,10-dideazatetrahydrofolic acid) is a thiopheneanalogue of lometrexol, is a second generation GARFT inhibitor(Mendelsohn L G. Investig. New Drugs (1996) 14: 287-294).

In 1991, Nair et al. demonstrated that contrary to the widely acceptednotion, polyglutamylation of classical antifolates is not essential foranti-tumor activity and further, that this metabolic transformation isactually undesirable because it may cause the loss of pharmacologicalcontrol and target specificity of the drug (Nair M G et al. J. Med. Chem(1991) 34: 222-227). This new finding let to the discovery of a numberof nonpolyglutamylatable classical antifolates (Nair M G et al. Proc.Amer. Assoc. Cancer. Research. (1998) 39:431).

U.S. Pat. No. 5,073,554 (Nair) describes methylene-1-deazaaminopterine(MDAM), a nonpolyglutamylatable antifolate compound. MDAM has beendeveloped as an experimental anticancer drug for the treatment of humansolid tumors (Cao S. et al. Clinical Cancer Research (1996) 2(4):707-712); Johansen M et al. Cancer Chemother Pharmacol. (2004)53(5):370-6). U.S. Pat. No. 5,550,128 (Nair et al) describes the activeenantiomer of MDAM as the one possessing the L-configuration.

Further investigation by Nair et al. of the metabolic disposition ofcertain non-polyglutamylatable antifolates led to the unexpected findingthat the presence of the 4-methyleneglutamate moiety modulates thebinding of such compounds to the liver enzyme aldehyde oxidase, whichmediates their oxidative deactivation to the corresponding 7-hydroxyderivatives (Cellular. Pharmacology (1996) 3: 29). U.S. Pat. No.5,912,251 (Nair) describes metabolically inert classical antifolates,including 4-Amino-4-deoxy-5,8,10-trideazapteroyl-4′-methylene glutamicacid, which are non-polyglutamylatable and non-hydroxylatable. They aresaid to be useful in the treatment of neoplastic disease (leukemia,ascetic and solid tumors), asthma and related anti-inflammatory disease,and for the treatment of rheumatoid arthritis and other autoimmunediseases.

wherein X is CH₂, CHCH₃, CH(CH₂CH₃), NH, or NCH₃.

wherein X is CH₂.

MTREX

In one embodiment, the compound of Formula (I) is provided as well as amethod for the treatment of a host with a disorder characterized bynon-neoplastic abnormal cell proliferation, non-asthmatic inflammationincluding, but not limited to, inflammatory bowel disease (e.g., Crohn'sdisease) and/or chronic obstructive pulmonary disease (COPD), and/ornon-rheumatoid arthritic auto-immune disease including, but not limitedto, psoriasis, osteoarthritis, and/or multiple sclerosis (MS),comprising administering an effective treatment amount of compound ofFormula (I):

or its pharmaceutically acceptable salt, ester, salt of an ester, amide,salt or an amide, prodrug, salt of a prodrug, or a steroisomeric,tautomeric or polymorphic form thereof; wherein

-   X is CH₂, CHCH₃, CH(CH₂CH₃), NH, NCH₃, or NR⁷-   R¹, R², R³, R⁴, and R⁷ are independently selected from H, optionally    substituted alkyl including lower alkyl, optionally substituted    alkenyl or alkynyl, acyl, —C(O)-(alkyl), —C(O)(lower alkyl),    —C(O)-(alkenyl), —C(O)-(alkynyl), —C(═Y³)V³, lipid, phospholipid,    carbohydrate, peptide, cholesterol, an amino acid residue or    derivative, an amino acid acyl residue or derivative or other    pharmaceutically acceptable leaving group that is capable of    providing a free amine when administered in vivo;-   R⁵ and R⁶ are independently selected from H, optionally substituted    alkyl including lower alkyl, optionally substituted alkenyl or    alkynyl, lipid, phospholipid, carbohydrate, peptide, cholesterol, an    amino acid residue or derivative, or other pharmaceutically    acceptable leaving group that is capable of providing a —C(═Y)V⁻ or    —C(═Y)VH moiety when administered in vivo;-   each Y¹, Y², and Y³ independently is O, S or NJ¹;-   each V¹ and V² independently is O, S or NJ¹-   each V³ independently is OH, OJ¹, SH, SJ¹, NH₂, NHJ¹, NJ¹J², CH₃,    CH₂R¹⁰¹, CHR¹⁰¹R¹⁰², or CR¹⁰¹R¹⁰²R¹⁰³;-   each J¹, J² and J³ independently are hydrogen, alkyl, alkenyl,    alkynyl, alkaryl, cycloalkyl, aryl, cycloaryl, heteroalkyl,    heterocycle, heteroaryl, hydroxyl, alkoxy, or amine; and-   each R¹⁰⁰, R¹⁰¹, R¹⁰², and R¹⁰³ are independently hydrogen, alkyl,    alkenyl, alkynyl, aryl, acyl, heteroaromatic, heteroaryl,    heteroalkyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro, SO₂,    SO₃, thioalkyl, or amino.

In another embodiment, a method for the treatment of psoriasis in ahost, including a human, is disclosed that involves administering aneffective amount of the compound of Formula (I), administered eitheralone or in combination and/or alternation with one or more otheranti-psoriasis agent, optionally in a pharmaceutically acceptablecarrier.

In another embodiment, a method for the treatment of inflammatory boweldisease in a host, including a human, is disclosed that involvesadministering an effective amount of the compound of Formula (I),administered either alone or in combination and/or alternation with oneor more other anti-inflammatory bowel disease agent, optionally in apharmaceutically acceptable carrier. In one embodiment, the inflammatorybowel disease is Crohn's disease.

In another preferred embodiment, a method for the treatment ofosteoarthritis in a host, including a human, is disclosed that involvesadministering an effective amount of the compound of Formula (I),administered either alone or in combination and/or alternation with oneor more other anti-osteoarthritis agent, optionally in apharmaceutically acceptable carrier.

In yet another preferred embodiment, a method for the treatment ofchronic obstructive pulmonary disease (COPD) in a host, including ahuman, is disclosed that involves administering an effective amount ofthe compound of Formula (I), administered either alone or in combinationand/or alternation with one or more other anti-COPD agent, optionally ina pharmaceutically acceptable carrier.

In another preferred embodiment, a method for the treatment of multiplesclerosis (MS) in a host, including a human, is disclosed that involvesadministering an effective amount of the compound of Formula (I),administered either alone or in combination and/or alternation with oneor more other anti-MS agent, optionally in a pharmaceutically acceptablecarrier.

In an alternative embodiment, the compound of Formula (II) is providedas well as a method for the treatment of a host with a disordercharacterized by abnormal cell proliferation, inflammation, and/orauto-immune disease, comprising administering an effective treatmentamount of a compound of Formula (II):

or its pharmaceutically acceptable salt, ester, salt of an ester, amide,salt or an amide, prodrug, salt of a prodrug, or a steroisomeric,tautomeric or polymorphic form thereof; wherein

-   X is CH₂, CHCH₃, CH(CH₂CH₃), NH, NCH₃, or NR⁷-   R¹, R², R³, R⁴, and R⁷ are independently selected from H, optionally    substituted alkyl including lower alkyl, optionally substituted    alkenyl or alkynyl, acyl, —C(O)-(alkyl), —C(O)(lower alkyl),    —C(O)-(alkenyl), —C(O)-(alkynyl), —C(═Y³)V³, lipid, phospholipid,    carbohydrate, peptide, cholesterol, an amino acid residue or    derivative, an amino acid acyl residue or derivative or other    pharmaceutically acceptable leaving group that is capable of    providing a free amine when administered in vivo;-   R⁵ and R⁶ are independently selected from H, optionally substituted    alkyl including lower alkyl, optionally substituted alkenyl or    alkynyl, lipid, phospholipid, carbohydrate, peptide, cholesterol, an    amino acid residue or derivative, or other pharmaceutically    acceptable leaving group that is capable of providing a —C(═Y)V⁻ or    —C(═Y)VH moiety when administered in vivo;-   each Y¹, Y², and Y³ independently is O, S or NJ¹;-   each V¹ and V² independently is O, S or NJ¹-   each V³ independently is OH, OJ¹, SH, SJ¹, NH₂, NHJ¹, NJ¹J², CH₃,    CH₂R¹⁰¹, CHR¹⁰¹R¹⁰², or CR¹⁰¹R¹⁰²R¹⁰³;-   each J¹, J² and J³ independently are hydrogen, alkyl, alkenyl,    alkynyl, alkaryl, cycloalkyl, aryl, cycloaryl, heteroalkyl,    heterocycle, heteroaryl, hydroxyl, alkoxy, or amine; and-   each R¹⁰⁰, R¹⁰¹, R¹⁰², and R¹⁰³ are independently hydrogen, alkyl,    alkenyl, alkynyl, aryl, acyl, heteroaromatic, heteroaryl,    heteroalkyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro, SO₂,    SO₃, thioalkyl, or amino;-   such that, if Y¹ and Y² are both oxygen, and V¹ and V² are both    oxygen, then at least one of R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ is not    H.

In one particular embodiment of the present invention, the compound ofFormula (II) is provided as well as a method for the treatment of a hostwith a disorder characterized by abnormal cell proliferation,inflammation, and/or auto-immune disease, comprising administering aneffective treatment amount of the compound of Formula (II) wherein:

-   X is NR⁷;-   R¹, R², R³, and R⁴ are independently selected from H, optionally    substituted alkyl including lower alkyl, optionally substituted    alkenyl or alkynyl, acyl, —C(O)-(alkyl), —C(O)(lower alkyl),    —C(O)-(alkenyl), —C(O)-(alkynyl), —C(═Y³)V³, lipid, phospholipid,    carbohydrate, peptide, cholesterol, an amino acid residue or    derivative, an amino acid acyl residue or derivative or other    pharmaceutically acceptable leaving group that is capable of    providing a free amine when administered in vivo;-   R⁷ is independently selected from an optionally substituted alkyl    including lower alkyl, optionally substituted alkenyl or alkynyl,    acyl, —C(O)-(alkyl), —C(O)(lower alkyl), —C(O)-(alkenyl),    —C(O)-(alkynyl), —C(═Y³)V³, lipid, phospholipid, carbohydrate,    peptide, cholesterol, an amino acid residue or derivative, an amino    acid acyl residue or derivative or other pharmaceutically acceptable    leaving group that is capable of providing a free amine when    administered in vivo;-   R⁵ and R⁶ are independently selected from H, optionally substituted    alkyl including lower alkyl, optionally substituted alkenyl or    alkynyl, lipid, phospholipid, carbohydrate, peptide, cholesterol, an    amino acid residue or derivative, or other pharmaceutically    acceptable leaving group that is capable of providing a —C(═Y)V⁻ or    —C(═Y)VH moiety when administered in vivo;-   each Y¹, Y², and Y³ independently is O, S or NJ¹;-   each V¹ and V² independently is O, S or NJ¹-   each V³ independently is OH, OJ¹, SH, SJ¹, NH₂, NHJ¹, NJ¹J², CH₃,    CH₂R¹⁰¹, CHR¹⁰¹R¹⁰², or CR¹⁰¹R¹⁰²R¹⁰³;-   each J¹, J² and J³ independently are hydrogen, alkyl, alkenyl,    alkynyl, alkaryl, cycloalkyl, aryl, cycloaryl, heteroalkyl,    heterocycle, heteroaryl, hydroxyl, alkoxy, or amine; and-   each R¹⁰⁰, R¹⁰¹, R¹⁰², and R¹⁰³ are independently hydrogen, alkyl,    alkenyl, alkynyl, aryl, acyl, heteroaromatic, heteroaryl,    heteroalkyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro, SO₂,    SO₃, thioalkyl, or amino.

In another particular embodiment of the present invention, the compoundof Formula (II) is provided as well as a method for the treatment of ahost with a disorder characterized by abnormal cell proliferation,inflammation, and/or auto-immune disease, comprising administering aneffective treatment amount of the compound of Formula (II) wherein:

-   X is NR⁷-   R¹, R², R³, R⁴ are H, optionally substituted alkyl including lower    alkyl, optionally substituted alkenyl or alkynyl, acyl,    —C(O)-(alkyl), —C(O)(lower alkyl), —C(O)-(alkenyl), —C(O)-(alkynyl),    —C(═Y³)V³, lipid, phospholipid, carbohydrate, peptide, cholesterol,    an amino acid residue or derivative, an amino acid acyl residue or    derivative or other pharmaceutically acceptable leaving group that    is capable of providing a free amine when administered in vivo;-   R⁷ is independently selected from an optionally substituted alkyl    including lower alkyl, optionally substituted alkenyl or alkynyl,    acyl, —C(O)-(alkyl), —C(O)(lower alkyl), —C(O)-(alkenyl),    —C(O)-(alkynyl), —C(═Y³)V³, lipid, phospholipid, carbohydrate,    peptide, cholesterol, an amino acid residue or derivative, an amino    acid acyl residue or derivative or other pharmaceutically acceptable    leaving group that is capable of providing a free amine when    administered in vivo;-   R⁵ and R⁶ are independently selected from H, optionally substituted    alkyl including lower alkyl, optionally substituted alkenyl or    alkynyl, lipid, phospholipid, carbohydrate, peptide, cholesterol, an    amino acid residue or derivative, or other pharmaceutically    acceptable leaving group that is capable of providing a —C(═Y)V⁻ or    —C(═Y)VH moiety when administered in vivo;-   each Y¹ and Y² are O-   each Y³ independently is O, S or NJ¹;-   each V¹ and V² independently is O;-   each V³ independently is OH, OJ¹, SH, SJ¹, NH₂, NHJ¹, NJ¹J², CH₃,    CH₂R¹⁰¹, CHR¹⁰¹R¹⁰², CR¹⁰¹R¹⁰²R¹⁰³;-   each J¹, J² and J³ independently are hydrogen, alkyl, alkenyl,    alkynyl, alkaryl, cycloalkyl, aryl, cycloaryl, heteroalkyl,    heterocycle, heteroaryl, hydroxyl, alkoxy, or amine; and-   each R¹⁰⁰, R¹⁰¹, R¹⁰², and R¹⁰³ are independently hydrogen, alkyl,    alkenyl, alkynyl, aryl, acyl, heteroaromatic, heteroaryl,    heteroalkyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro, SO₂,    SO₃, thioalkyl, or amino.

In another particular embodiment of the present invention, the compoundof Formula (II) is provided as well as a method for the treatment of ahost with a disorder characterized by abnormal cell proliferation,inflammation, and/or auto-immune disease, comprising administering aneffective treatment amount of the compound of Formula (II) wherein:

-   X is CH₂, CHCH₃, CH(CH₂CH₃), NH, NCH₃, or NR⁷-   R¹, R², R³, R⁴, and R⁷ are independently selected from H, optionally    substituted alkyl including lower alkyl, optionally substituted    alkenyl or alkynyl, acyl, —C(O)-(alkyl), —C(O)(lower alkyl),    —C(O)-(alkenyl), —C(O)-(alkynyl), —C(═Y³)V³, lipid, phospholipid,    carbohydrate, peptide, cholesterol, an amino acid residue or    derivative, an amino acid acyl residue or derivative or other    pharmaceutically acceptable leaving group that is capable of    providing a free amine when administered in vivo;-   wherein at least one of R¹, R², R³, R⁴, and R⁷ is not H;-   R⁵ and R⁶ are independently selected from H, optionally substituted    alkyl including lower alkyl, optionally substituted alkenyl or    alkynyl, lipid, phospholipid, carbohydrate, peptide, cholesterol, an    amino acid residue or derivative, or other pharmaceutically    acceptable leaving group that is capable of providing a —C(═Y)V⁻ or    —C(═Y)VH moiety when administered in vivo;-   each Y¹, Y², and Y³ independently is O, S or NJ¹;-   each V¹ and V² independently is O, S or NJ¹-   each V³ independently is OH, OJ¹, SH, SJ¹, NH₂, NHJ¹, NJ¹J², CH₃,    CH₂R¹⁰¹, CHR¹⁰¹R¹⁰², or CR¹⁰¹R¹⁰²R¹⁰³;-   each J¹, J² and J³ independently are hydrogen, alkyl, alkenyl,    alkynyl, alkaryl, cycloalkyl, cycloaryl, heteroalkyl, heterocycle,    heteroaryl, hydroxyl, alkoxy, or amine; and-   each R¹⁰⁰, R¹⁰¹, R¹⁰², and R¹⁰³ are independently hydrogen, alkyl,    alkenyl, alkynyl, aryl, acyl, heteroaromatic, heteroaryl,    heteroalkyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro, SO₂,    SO₃, thioalkyl, or amino.

In yet another particular embodiment of the present invention, thecompound of Formula (II) is provided as well as a method for thetreatment of a host with a disorder characterized by abnormal cellproliferation, inflammation, and/or auto-immune disease, comprisingadministering an effective treatment amount of the compound of Formula(II) wherein:

-   X is CH₂, CHCH₃, CH(CH₂CH₃), NH, NCH₃, or NR⁷-   R¹, R², R³, R⁴, and R⁷ are independently selected from H, optionally    substituted alkyl including lower alkyl, optionally substituted    alkenyl or alkynyl, acyl, —C(O)-(alkyl), —C(O)(lower alkyl),    —C(O)-(alkenyl), —C(O)-(alkynyl), —C(═Y³)V³, lipid, phospholipid,    carbohydrate, peptide, cholesterol, an amino acid residue or    derivative, an amino acid acyl residue or derivative or other    pharmaceutically acceptable leaving group that is capable of    providing a free amine when administered in vivo;-   R⁵ and R⁶ are independently selected from H, optionally substituted    alkyl including lower alkyl, optionally substituted alkenyl or    alkynyl, lipid, phospholipid, carbohydrate, peptide, cholesterol, an    amino acid residue or derivative, or other pharmaceutically    acceptable leaving group that is capable of providing a —C(═Y)V⁻ or    —C(═Y)VH moiety when administered in vivo;-   each Y¹, Y², and Y³ independently is O, S or NJ¹;-   each V¹ and V² independently is O, S or NJ¹;-   wherein at least one of Y¹, Y², V¹ and V² is not O;-   each V³ independently is OH, OJ¹, SH, SJ¹, NH₂, NHJ¹, NJ¹J², CH₃,    CH₂R¹⁰¹, CHR¹⁰¹R¹⁰², or CR¹⁰¹R¹⁰²R¹⁰³;-   each J¹, J² and J³ independently are hydrogen, alkyl, alkenyl,    alkynyl, alkaryl, cycloalkyl, aryl, cycloaryl, heteroalkyl,    heterocycle, heteroaryl, hydroxyl, alkoxy, or amine; and-   each R¹⁰⁰, R¹⁰¹, R¹⁰², and R¹⁰³ are independently hydrogen, alkyl,    alkenyl, alkynyl, aryl, acyl, heteroaromatic, heteroaryl,    heteroalkyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro, SO₂,    SO₃, thioalkyl, or amino.

In yet another particular embodiment of the present invention, thecompound of Formula (II) is provided as well as a method for thetreatment of a host with a disorder characterized by abnormal cellproliferation, inflammation, and/or auto-immune disease, comprisingadministering an effective treatment amount of the compound of Formula(II) wherein:

-   X is CH₂, CHCH₃, CH(CH₂CH₃), NH, NCH₃, or NR⁷-   R¹, R², R³, R⁴, and R⁷ are independently selected from H, optionally    substituted alkyl including lower alkyl, optionally substituted    alkenyl or alkynyl, acyl, —C(O)-(alkyl), —C(O)(lower alkyl),    —C(O)-(alkenyl), —C(O)-(alkynyl), —C(═Y³)V³, lipid, phospholipid,    carbohydrate, peptide, cholesterol, an amino acid residue or    derivative, an amino acid acyl residue or derivative or other    pharmaceutically acceptable leaving group that is capable of    providing a free amine when administered in vivo;-   R⁵ and R⁶ are independently selected from H, optionally substituted    alkyl including lower alkyl, optionally substituted alkenyl or    alkynyl, lipid, phospholipid, carbohydrate, peptide, cholesterol, an    amino acid residue or derivative, or other pharmaceutically    acceptable leaving group that is capable of providing a —C(═Y)V⁻ or    —C(═Y)VH moiety when administered in vivo;-   wherein at least one of R⁵ and R⁶ is not H;-   each Y¹, Y², and Y³ independently is O, S or NJ¹;-   each V¹ and V² independently is O, S or NJ¹-   each V³ independently is OH, OJ¹, SH, SJ¹, NH₂, NHJ¹, NJ¹J², CH₃,    CH₂R¹⁰¹, CHR¹⁰¹R¹⁰², or CR¹⁰¹R¹⁰²R¹⁰³;-   each J¹, J² and J³ independently are hydrogen, alkyl, alkenyl,    alkynyl, alkaryl, cycloalkyl, aryl, cycloaryl, heteroalkyl,    heterocycle, heteroaryl, hydroxyl, alkoxy, or amine; and-   each R¹⁰⁰, R¹⁰¹, R¹⁰², and R¹⁰³ are independently hydrogen, alkyl,    alkenyl, alkynyl, aryl, acyl, heteroaromatic, heteroaryl,    heteroalkyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro, SO₂,    SO₃, thioalkyl, or amino;-   such that, if Y¹ and Y² are both oxygen, and V¹ and V² are both    oxygen, then at least one of R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ is not    H.

In yet another particular embodiment of the present invention, thecompound of Formula (II) is provided as well as a method for thetreatment of a host with a disorder characterized by abnormal cellproliferation, inflammation, and/or auto-immune disease, comprisingadministering an effective treatment amount of the compound of Formula(II) wherein:

-   at least one of R¹, R², R³, R⁴, and R⁷ is selected from an    optionally substituted alkyl including lower alkyl, optionally    substituted alkenyl or alkynyl, acyl, —C(O)-(alkyl), —C(O)(lower    alkyl), —C(O)-(alkenyl), —C(O)-(alkynyl), —C(═Y³)V³, lipid,    phospholipid, carbohydrate, peptide, cholesterol, an amino acid    residue or derivative, an amino acid acyl residue or derivative or    other pharmaceutically acceptable leaving group that is capable of    providing a free amine when administered in vivo;-   each Y¹ and Y² is O; and-   each V¹ and V² is O.

In another particular embodiment of the present invention, the compoundof Formula (II) is provided as well as a method for the treatment of ahost with a disorder characterized by abnormal cell proliferation,inflammation, and/or auto-immune disease, comprising administering aneffective treatment amount of the compound of Formula (II) wherein:

-   at least one of R¹, R², R³, R⁴, and R⁷ is selected from an    optionally substituted alkyl including lower alkyl, optionally    substituted alkenyl or alkynyl, acyl, —C(O)-(alkyl), —C(O)(lower    alkyl), —C(O)-(alkenyl), —C(O)-(alkynyl), —C(═Y³)V³, an amino acid    residue or derivative, or an amino acid acyl residue or derivative;-   each Y¹ and Y² is O; and-   each V¹ and V² is O.

In another particular embodiment of the present invention, the compoundof Formula (II) is provided as well as a method for the treatment of ahost with a disorder characterized by abnormal cell proliferation,inflammation, and/or auto-immune disease, comprising administering aneffective treatment amount of the compound of Formula (II) wherein:

-   at least one of R¹, R², R³, R⁴, and R⁷ is selected from an    optionally acyl, —C(O)-(alkyl), —C(O)(lower alkyl), —C(O)-(alkenyl),    —C(O)-(alkynyl), —C(═Y³)V³, or an amino acid acyl residue or    derivative;-   each Y¹ and Y² is O; and-   each V¹ and V² is O.

In yet another particular embodiment of the present invention, thecompound of Formula (II) is provided as well as a method for thetreatment of a host with a disorder characterized by abnormal cellproliferation, inflammation, and/or auto-immune disease, comprisingadministering an effective treatment amount of the compound of Formula(II) wherein:

-   at least one of R⁵ and R⁶ is selected from an optionally substituted    alkyl including lower alkyl, optionally substituted alkenyl or    alkynyl, lipid, phospholipid, carbohydrate, peptide, cholesterol, an    amino acid residue or derivative, or other pharmaceutically    acceptable leaving group that is capable of providing a —C(═Y)V⁻ or    —C(═Y)VH moiety when administered in vivo;-   each Y¹ and Y² is O; and-   each V¹ and V² is O.

In another particular embodiment of the present invention, the compoundof Formula (II) is provided as well as a method for the treatment of ahost with a disorder characterized by abnormal cell proliferation,inflammation, and/or auto-immune disease, comprising administering aneffective treatment amount of the compound of Formula (II) wherein:

-   at least one of R⁵ and R⁶ is selected from an optionally substituted    alkyl including lower alkyl, optionally substituted alkenyl or    alkynyl, an amino acid residue or derivative, or other    pharmaceutically acceptable leaving group that is capable of    providing a —C(═Y)V⁻ or —C(═Y)VH moiety when administered in vivo;-   each Y¹ and Y² is O; and-   each V¹ and V² is O.

In another particular embodiment of the present invention, the compoundof Formula (II) is provided as well as a method for the treatment of ahost with a disorder characterized by abnormal cell proliferation,inflammation, and/or auto-immune disease, comprising administering aneffective treatment amount of the compound of Formula (II) wherein:

-   at least one of R⁵ and R⁶ is selected from an optionally substituted    alkyl including lower alkyl, optionally substituted alkenyl or    alkynyl, or an amino acid residue or derivative;-   each Y¹ and Y² is O; and-   each V¹ and V² is O.

In one embodiment, a method for the treatment of abnormal cellproliferation in a host, including a human, is disclosed that involvesadministering an effective amount of the compound of Formula (II),administered either alone or in combination and/or alternation with oneor more other anti-abnormal cell proliferation agent, optionally in apharmaceutically acceptable carrier.

In one embodiment, a method for the treatment of abnormal cellproliferation in a host, including a human, is disclosed that involvesadministering an effective amount of the compound of Formula (II),administered either alone or in combination and/or alternation with oneor more other agent effective in the treatment of an autoimmunedisorder.

In another embodiment, a method for the treatment of an inflammatorydisease in a host, including a human, is disclosed that involvesadministering an effective amount of a of the compound of Formula (II),administered either alone or in combination and/or alternation with oneor more other anti-inflammatory agent, optionally in a pharmaceuticallyacceptable carrier, optionally in a pharmaceutically acceptable carrier.

In another embodiment, a method for the treatment of psoriasis in ahost, including a human, is disclosed that involves administering aneffective amount of the compound of Formula (II), administered eitheralone or in combination and/or alternation with one or more otheranti-psoriasis agent, optionally in a pharmaceutically acceptablecarrier.

In another embodiment, a method for the treatment of inflammatory boweldisease in a host, including a human, is disclosed that involvesadministering an effective amount of the compound of Formula (II),administered either alone or in combination and/or alternation with oneor more other anti-inflammatory bowel disease agent, optionally in apharmaceutically acceptable carrier. In one embodiment, the inflammatorybowel disease is Crohn's disease.

In another preferred embodiment, a method for the treatment ofosteoarthritis in a host, including a human, is disclosed that involvesadministering an effective amount of the compound of Formula (II),administered either alone or in combination and/or alternation with oneor more other anti-osteoarthritis agent, optionally in apharmaceutically acceptable carrier.

In yet another preferred embodiment, a method for the treatment ofchronic obstructive pulmonary disease (COPD) in a host, including ahuman, is disclosed that involves administering an effective amount ofthe compound of Formula (II), administered either alone or incombination and/or alternation with one or more other anti-COPD agent,optionally in a pharmaceutically acceptable carrier.

In another preferred embodiment, a method for the treatment of multiplesclerosis (MS) in a host, including a human, is disclosed that involvesadministering an effective amount of the compound of Formula (II),administered either alone or in combination and/or alternation with oneor more other anti-MS agent, optionally in a pharmaceutically acceptablecarrier.

Other particular embodiments include:

A compound of the formula:

or its pharmaceutically acceptable salt, wherein

-   X is CH₂, CHCH₃, CH(CH₂CH₃), NH, NCH₃, or N⁷-   R¹, R², R³, R⁴, and R⁷ are independently selected from H, optionally    substituted alkyl, optionally substituted alkenyl or alkynyl, acyl,    —C(O)-(alkyl), —C(O)-(alkenyl), —C(O)-(alkynyl), —C(═Y³)V³, lipid,    phospholipid, carbohydrate, peptide, cholesterol, an amino acid    residue or an amino acid acyl residue;-   R⁵ and R⁶ are independently selected from H, optionally substituted    alkyl, optionally substituted alkenyl or alkynyl, lipid,    phospholipid, carbohydrate, peptide, cholesterol, an amino acid    residue or derivative, or other pharmaceutically acceptable leaving    group that is capable of providing a —C(═Y)V⁻ or —C(═Y)VH moiety    when administered in vivo;-   each Y¹, Y², and Y³ independently is O, S or NJ¹;-   each V¹ and V² independently is O, S or NJ¹-   each V³ independently is OH, OJ¹, SH, SJ¹, NH₂, NHJ¹, NJ¹J², CH₃,    CH₂R¹⁰¹, CHR¹⁰¹R¹⁰², or CR¹⁰¹R¹⁰²R¹⁰³;-   each J¹, J² and J³ independently are hydrogen, alkyl, alkenyl,    alkynyl, alkaryl, cycloalkyl, aryl, cycloaryl, heteroalkyl,    heterocycle, heteroaryl, hydroxyl, alkoxy, or amine; and-   each R¹⁰⁰, R¹⁰¹, R¹⁰², and R¹⁰³ are independently hydrogen, alkyl,    alkenyl, alkynyl, aryl, acyl, heteroaromatic, heteroaryl,    heteroalkyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro, SO₂,    SO₃, thioalkyl, or amino;-   such that, if Y¹ and Y² are both oxygen, and V¹ and V² are both    oxygen, then at least one of R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ is not    H.

A method for the treatment of abnormal cell proliferation, comprisingadministering an effective amount of a compound of the formula below incombination with an anti-neoplastic agent:

or its pharmaceutically acceptable salt, wherein

-   X is CH₂, CHCH₃, CH(CH₂CH₃), NH, NCH₃, or NR⁷-   R¹, R², R³, R⁴, and R⁷ are independently selected from H, optionally    substituted alkyl, optionally substituted alkenyl or alkynyl, acyl,    —C(O)-(alkyl), —C(O)-(alkenyl), —C(O)-(alkynyl), —C(═Y³)V³, lipid,    phospholipid, carbohydrate, peptide, cholesterol, an amino acid    residue or an amino acid acyl residue;-   R⁵ and R⁶ are independently selected from H, optionally substituted    alkyl, optionally substituted alkenyl or alkynyl, lipid,    phospholipid, carbohydrate, peptide, cholesterol, an amino acid    residue or derivative, or other pharmaceutically acceptable leaving    group that is capable of providing a —C(═Y)V⁻ or —C(═Y)VH moiety    when administered in vivo;-   each Y¹, Y², and Y³ independently is O, S or NJ¹;-   each V¹ and V² independently is O, S or NJ¹-   each V³ independently is OH, OJ¹, SH, SJ¹, NH₂, NHJ¹, NJ¹J², CH₃,    CH₂R¹⁰¹, CHR¹⁰¹R¹⁰², or CR¹⁰¹R¹⁰²R¹⁰³;-   each J¹, J² and J³ independently are hydrogen, alkyl, alkenyl,    alkynyl, alkaryl, cycloalkyl, aryl, cycloaryl, heteroalkyl,    heterocycle, heteroaryl, hydroxyl, alkoxy, or amine; and-   each R¹⁰⁰, R¹⁰¹, R¹⁰², and R¹⁰³ are independently hydrogen, alkyl,    alkenyl, alkynyl, aryl, acyl, heteroaromatic, heteroaryl,    heteroalkyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro, SO₂,    SO₃, thioalkyl, or amino;

A method to treat a disease or disorder characterized by abnormal cellproliferation in a host, comprising administering an effective amount ofthe compound of Formula (II).

or its pharmaceutically acceptable salt; wherein

-   X is CH₂, CHCH₃, CH(CH₂CH₃), NH, NCH₃, or NR⁷-   R¹, R², R³, R⁴, and R⁷ are independently selected from H, optionally    substituted alkyl, optionally substituted alkenyl or alkynyl, acyl,    —C(O)-(alkyl), —C(O)-(alkenyl), —C(O)-(alkynyl), —C(═Y³)V³, lipid,    phospholipid, carbohydrate, peptide, cholesterol, an amino acid    residue or an amino acid acyl residue;-   R⁵ and R⁶ are independently selected from H, optionally substituted    alkyl, optionally substituted alkenyl or alkynyl, lipid,    phospholipid, carbohydrate, peptide, cholesterol, an amino acid    residue or derivative, or other pharmaceutically acceptable leaving    group that is capable of providing a —C(═Y)V⁻ or —C(═Y)VH moiety    when administered in vivo;-   each Y¹, Y², and Y³ independently is O, S or NJ¹;-   each V¹ and V² independently is O, S or NJ¹-   each V³ independently is OH, OJ¹, SH, SJ¹, NH₂, NHJ¹, NJ¹J², CH₃,    CH₂R¹⁰¹, CHR¹⁰¹R¹⁰², CR¹⁰¹R¹⁰²R¹⁰³;-   each J¹, J² and J³ independently are hydrogen, alkyl, alkenyl,    alkynyl, alkaryl, cycloalkyl, aryl, cycloaryl, heteroalkyl,    heterocycle, heteroaryl, hydroxyl, alkoxy, or amine; and-   each R¹⁰⁰, R¹⁰¹, R¹⁰², and R¹⁰³ are independently hydrogen, alkyl,    alkenyl, alkynyl, aryl, acyl, heteroaromatic, heteroaryl,    heteroalkyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro, SO₂,    SO₃, thioalkyl, or amino;-   such that, when the disorder is a tumor, if Y¹ and Y² are both    oxygen, and V¹ and V² are both oxygen, then at least one of R¹, R²,    R³, R⁴, R⁵, R⁶, and R⁷ is not H.

A method to treat an inflammatory disease or disorder in a host,comprising administering an effective amount of the compound of Formula(II).

or its pharmaceutically acceptable salt; wherein

-   X is CH₂, CHCH₃, CH(CH₂CH₃), NH, NCH₃, or NR⁷-   R¹, R², R³, R⁴, and R⁷ are independently selected from H, optionally    substituted alkyl, optionally substituted alkenyl or alkynyl, acyl,    —C(O)-(alkyl), —C(O)-(alkenyl), —C(O)-(alkynyl), —C(═Y³)V³, lipid,    phospholipid, carbohydrate, peptide, cholesterol, an amino acid    residue or an amino acid acyl residue;-   R⁵ and R⁶ are independently selected from H, optionally substituted    alkyl, optionally substituted alkenyl or alkynyl, lipid,    phospholipid, carbohydrate, peptide, cholesterol, an amino acid    residue or derivative, or other pharmaceutically acceptable leaving    group that is capable of providing a —C(═Y)V⁻ or —C(═Y)VH moiety    when administered in vivo;-   each Y¹, Y², and Y³ independently is O, S or NJ¹;-   each V¹ and V² independently is O, S or NJ¹-   each V³ independently is OH, OJ¹, SH, SJ¹, NH₂, NHJ¹, NJ¹J², CH₃,    CH₂R¹⁰¹, CHR¹⁰¹R¹⁰², CR¹⁰²R¹⁰²R¹⁰³;-   each J¹, J² and J³ independently are hydrogen, alkyl, alkenyl,    alkynyl, alkaryl, cycloalkyl, aryl, cycloaryl, heteroalkyl,    heterocycle, heteroaryl, hydroxyl, alkoxy, or amine; and-   each R¹⁰⁰, R¹⁰¹, R¹⁰², and R¹⁰³ are independently hydrogen, alkyl,    alkenyl, alkynyl, aryl, acyl, heteroaromatic, heteroaryl,    heteroalkyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro, SO₂,    SO₃, thioalkyl, or amino;-   such that, if Y¹ and Y² are both oxygen, and V¹ and V² are both    oxygen, then at least one of R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ is not    H.

A method to treat an autoimmune disease or disorder in a host,comprising administering an effective amount of the compound of Formula(II)

or its pharmaceutically acceptable salt; wherein

-   X is CH₂, CHCH₃, CH(CH₂CH₃), NH, NCH₃, or NR⁷-   R¹, R², R³, R⁴, and R⁷ are independently selected from H, optionally    substituted alkyl, optionally substituted alkenyl or alkynyl, acyl,    —C(O)-(alkyl), —C(O)-(alkenyl), —C(O)-(alkynyl), —C(═Y³)V³, lipid,    phospholipid, carbohydrate, peptide, cholesterol, an amino acid    residue or an amino acid acyl residue;-   R⁵ and R⁶ are independently selected from H, optionally substituted    alkyl, optionally substituted alkenyl or alkynyl, lipid,    phospholipid, carbohydrate, peptide, cholesterol, an amino acid    residue or derivative, or other pharmaceutically acceptable leaving    group that is capable of providing a —C(═Y)V⁻ or —C(═Y)VH moiety    when administered in vivo;-   each Y¹, Y², and Y³ independently is O, S or NJ¹;-   each V¹ and V² independently is O, S or NJ¹-   each V³ independently is OH, OJ¹, SH, SJ¹, NH₂, NHJ¹, NJ¹J², CH₃,    CH₂R¹⁰¹, CHR¹⁰¹R¹⁰², or CR¹⁰¹R¹⁰²R¹⁰³;-   each J¹, J² and J³ independently are hydrogen, alkyl, alkenyl,    alkynyl, alkaryl, cycloalkyl, aryl, cycloaryl, heteroalkyl,    heterocycle, heteroaryl, hydroxyl, alkoxy, or amine; and-   each R¹⁰⁰, R¹⁰¹, R¹⁰², and R¹⁰³ are independently hydrogen,alkyl,    alkenyl, alkynyl, aryl, acyl, heteroaromatic, heteroaryl,    heteroalkyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro, SO₂,    SO₃, thioalkyl, or amino;-   such that, if Y¹ and Y² are both oxygen, and V¹ and V² are both    oxygen, then at least one of R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ is not    H.

A method of treating psoriasis, comprising administering an effectiveamount of the compound of Formula (I):

or its pharmaceutically acceptable salt; wherein

-   X is CH₂, CHCH₃, CH(CH₂CH₃), NH, NCH₃, or NR⁷-   R¹, R², R³, R⁴, and R⁷ are independently selected from H, optionally    substituted alkyl, optionally substituted alkenyl or alkynyl, acyl,    —C(O)-(alkyl), —C(O)-(alkenyl), —C(O)-(alkynyl), —C(═Y³)V³, lipid,    phospholipid, carbohydrate, peptide, cholesterol, an amino acid    residue or an amino acid acyl residue;-   R⁵ and R⁶ are independently selected from H, optionally substituted    alkyl, optionally substituted alkenyl or alkynyl, lipid,    phospholipid, carbohydrate, peptide, cholesterol, an amino acid    residue or derivative, or other pharmaceutically acceptable leaving    group that is capable of providing a —C(═Y)V⁻ or —C(═Y)VH moiety    when administered in vivo;-   each Y¹, Y², and Y³ independently is O, S or NJ¹;-   each V¹ and V² independently is O, S or NJ¹-   each V³ independently is OH, OJ¹, SH, SJ¹, NH₂, NHJ¹, NJ¹J², CH₃,    CH₂R¹⁰¹, CHR¹⁰¹R¹⁰², or CR¹⁰¹R¹⁰²R¹⁰³;-   each J¹, J² and J³ independently are hydrogen, alkyl, alkenyl,    alkynyl, alkaryl, cycloalkyl, aryl, cycloaryl, heteroalkyl,    heterocycle, heteroaryl, hydroxyl, alkoxy, or amine; and-   each R¹⁰⁰, R¹⁰¹, R¹⁰², and R¹⁰³ are independently hydrogen, alkyl,    alkenyl, alkynyl, aryl, acyl, heteroaromatic, heteroaryl,    heteroalkyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro, SO₂,    SO₃, thioalkyl, or amino.

A method of treating inflammatory bowel disease, comprisingadministering an effective amount of the compound of Formula (I):

or its pharmaceutically acceptable salt; wherein

-   X is CH₂, CHCH₃, CH(CH₂CH₃), NH, NCH₃, or NR⁷-   R¹, R², R³, R⁴, and R⁷ are independently selected from H, optionally    substituted alkyl, optionally substituted alkenyl or alkynyl, acyl,    —C(O)-(alkyl), —C(O)-(alkenyl), —C(O)-(alkynyl), —C(═Y³)V³, lipid,    phospholipid, carbohydrate, peptide, cholesterol, an amino acid    residue or an amino acid acyl residue;-   R⁵ and R⁶ are independently selected from H, optionally substituted    alkyl, optionally substituted alkenyl or alkynyl, lipid,    phospholipid, carbohydrate, peptide, cholesterol, an amino acid    residue or derivative, or other pharmaceutically acceptable leaving    group that is capable of providing a —C(═Y)V⁻ or —C(═Y)VH moiety    when administered in vivo;-   each Y¹, Y², and Y³ independently is O, S or NJ¹;-   each V¹ and V² independently is O, S or NJ¹-   each V³ independently is OH, OJ¹, SH, SJ¹, NH₂, NHJ¹, NJ¹J², CH₃,    CH₂R¹⁰¹, CHR¹⁰¹R¹⁰², or CR¹⁰¹R¹⁰²R¹⁰³;-   each J¹, J² and J³ independently are hydrogen, alkyl, alkenyl,    alkynyl, alkaryl, cycloalkyl, aryl, cycloaryl, heteroalkyl,    heterocycle, heteroaryl, hydroxyl, alkoxy, or amine; and-   each R¹⁰⁰, R¹⁰¹, R¹⁰², and R¹⁰³ are independently hydrogen, alkyl,    alkenyl, alkynyl, aryl, acyl, heteroaromatic, heteroaryl,    heteroalkyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro, SO₂,    SO₃, thioalkyl, or amino;

A method of treating multiple sclerosis in a host, comprisingadministering an effective amount of the compound of Formula (I):

or its pharmaceutically acceptable salt; wherein

-   X is CH₂, CHCH₃, CH(CH₂CH₃), NH, NCH₃, or NR⁷-   R¹, R², R³, R⁴, and R⁷ are independently selected from H, optionally    substituted alkyl, optionally substituted alkenyl or alkynyl, acyl,    —C(O)-(alkyl), —C(O)-(alkenyl), —C(O)-(alkynyl), —C(═Y³)V³, lipid,    phospholipid, carbohydrate, peptide, cholesterol, an amino acid    residue or an amino acid acyl residue;-   R⁵ and R⁶ are independently selected from H, optionally substituted    alkyl, optionally substituted alkenyl or alkynyl, lipid,    phospholipid, carbohydrate, peptide, cholesterol, an amino acid    residue or derivative, or other pharmaceutically acceptable leaving    group that is capable of providing a —C(═Y)V⁻ or —C(═Y)VH moiety    when administered in vivo;-   each Y¹, Y², and Y³ independently is O, S or NJ¹;-   each V¹ and V² independently is O, S or NJ¹-   each V³ independently is OH, OJ¹, SH, SJ¹, NH₂, NHJ¹, NJ¹J², CH₃,    CH₂R¹⁰¹, CHR¹⁰¹R¹⁰², or CR¹⁰¹R¹⁰²R¹⁰³;-   each J¹, J² and J³ independently are hydrogen, alkyl, alkenyl,    alkynyl, alkaryl, cycloalkyl, aryl, cycloaryl, heteroalkyl,    heterocycle, heteroaryl, hydroxyl, alkoxy, or amine; and-   each R¹⁰⁰, R¹⁰¹, R¹⁰², and R¹⁰³ are independently hydrogen, alkyl,    alkenyl, alkynyl, aryl, acyl, heteroaromatic, heteroaryl,    heteroalkyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro, SO₂,    SO₃, thioalkyl, or amino;-   such that, if Y¹ and Y² are both oxygen, and V¹ and V² are both    oxygen, then at least one of R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ is not    H.

A pharmaceutically acceptable salt of a compound of the formula:

wherein X is CH₂, CHCH₃, CH(CH₂CH₃), NH, or NCH₃.

II. Definitions

The term “alkyl” as used herein, unless otherwise specified, refers to asaturated straight, branched, or cyclic, primary, secondary, or tertiaryhydrocarbon of, for example, C₁ to C₁₀, and specifically includesmethyl, trifluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, butyl,isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl,isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl,2,2-dimethylbutyl, and 2,3-dimethylbutyl. The term includes bothsubstituted and unsubstantiated alkyl groups. Moieties with which thealkyl group can be substituted with one or more substituents areselected from the group consisting of halo, including Cl, F, Br and I soas to form, for e.g., CF₃, 2-Br-ethyl, CH₂F, CH₂Cl, CH₂CF₃, or CF₂CF₃;hydroxyl, for e.g. CH₂OH; amino, for eg., CH₂NH₂, CH₂NHCH₃, orCH₂N(CH₃)₂; carboxylate; carboxamido; alkylamino; arylamino; alkoxy;aryloxy; nitro; azido, for eg., CH₂N₃; cyano, for eg., CH₂CN; thio;sulfonic acid; sulfate; phosphonic acid; phosphate; and phosphonate,either unprotected or protected as necessary, known to those skilled inthe art, for eg., as taught in Greene et al., Protective Groups inOrganic Synthesis, John Wiley and Sons, Second Edition (1991),incorporated herein by reference.

The term “lower alkyl”, as used herein, and unless otherwise specified,refers to a C₁ to C₆ saturated straight, branched, or if appropriate, acyclic (for example, cyclopropyl) alkyl group, including bothsubstituted and unsubstituted forms. Unless otherwise specificallystated in this application, when alkyl is a suitable moiety, lower alkylis preferred. Similarly, when alkyl or lower alkyl is a suitable moiety,unsubstituted alkyl or lower alkyl is preferred.

The terms alkenyl and alkynyl refer to alkyl moieties wherein at leastone saturated C—C bond is replaced by a double or triple bond. Thus,(C₂-C₆)alkenyl can be vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl. Similarly,(C₂-C₆)alkynyl can be ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl.

As used herein, with exceptions as noted, “aryl” is intended to mean anystable monocyclic, bicyclic or tricyclic carbon ring of up to 8 membersin each ring, wherein at least one ring is aromatic as defined by theHuckel 4n+2 rule. Examples of aryl ring systems include phenyl,naphthyl, tetrahydronaphthyl, and biphenyl. The aryl group can besubstituted with one or more moieties selected from the group consistingof hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro,cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, orphosphonate, either unprotected, or protected as necessary, as known tothose skilled in the art, for example, as taught in Greene, et al.,Protective Groups in Organic Synthesis, John Wiley and Sons, SecondEdition, 1991.

The terms “aralkyl” and “arylalkyl”, as used herein, and unlessotherwise specified, refers to an aryl group as defined above linked tothe molecule through an alkyl group as defined above.

The term “alkaryl” and “alkylaryl”, as used herein, and unless otherwisespecified, refers to an alkyl group as defined above linked to themolecule through an aryl group as defined above.

The term alkoxy, as used herein, and unless otherwise specified, refersto a moiety of the structure —O-alkyl, wherein alkyl is as definedabove.

The term “halo” as used herein includes bromo, chloro, iodo and fluoro.

The term “acyl” refers to a carboxylic acid ester in which thenon-carbonyl moiety of the ester group is selected from straight,branched, or cyclic alkyl or lower alkyl; alkoxyalkyl includingmethoxymethyl; aralkyl including benzyl; aryloxyalkyl such asphenoxymethyl; aryl including phenyl optionally substituted withhalogen; C₁-C₆ alkyl or C₁-C₆ alkoxy; sulfonate esters such as alkyl oraralkyl sulphonyl including methanesulfonyl; the mono-, di- ortriphosphate ester; trityl or monomethoxytrityl; substituted benzyl;trialkylsilyl as, for e.g., dimethyl-t-butylsilyl ordiphenylmethylsilyl. Aryl groups in the esters optimally comprise aphenyl group.

The term “lower acyl” refers to an acyl group in which the non-carbonylmoiety is lower alkyl.

The term amino, as used herein, refers to a moiety represented by thestructure —NR₂, and includes primary amines, and secondary, and tertiaryamines substituted by alkyl (i.e. alkylamino). Thus, R₂ may representtwo hydrogens, two alkyl moieties, or one hydrogen and one alkyl moiety.

The terms “alkylamino” and “arylamino” refer to an amino group that hasone or two alkyl or aryl substituents, respectively.

The term “protected” as used herein and, unless otherwise defined,refers to a group that is added to an oxygen, nitrogen or phosphorusatom to prevent its further reaction or for other purposes. Numerousoxygen and nitrogen protecting groups are known to those skilled in theart of organic synthesis.

The term amido, as used herein, refers to a moiety represented by thestructure —C(O)NR₂, wherein R₂ is as defined for amino.

As used herein, an “amino acid” is a natural amino acid residue (e.g.Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Hyl, Hyp, Ile, Leu Lys,Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val) in D or L form, or anunnatural amino acid (e.g. phosphoserine; phosphothreonine;phosphotyrosine; gamma-carboxyglutamate; hippuric acid;octahydroindole-2-carboxylic acid; statin;1,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid; penicillamine;ornithine; citrulline; a-methyl-alanine; para-benzoylphenylalanine;phenylglycine; propargyl-glycine; sarcosine; and tert-butylglycine)residue having one or more open valences. Other unnatural amino acidsinclude those represented by the formula NH₂ (CH₂)_(y) COOH, whereiny=2-20, and preferably 2-12, and include the aminoalkanoic acids such asc-amino caproic acid (H₂N—(CH₂)₅—COOH).

The term also comprises natural and unnatural amino acids bearing aminoprotecting groups such as acetyl, acyl, trifluoroacetyl, andbenzyloxycarbonyl), as well as natural and unnatural amino acidsprotected at carboxy with protecting groups such as a C₁-C₆ alkyl,phenyl or benzyl ester and amide. Other suitable amino and carboxyprotecting groups are known to those skilled in the art. See forexample, T. W. Greene, Protecting Groups in Organic Synthesis; Wiley:New York, 1981; D. Voet, Biochemistry, Wiley: New York, 1990; L. Stryer,Biochemistry, (3^(rd) Ed), W. H. Freeman and Co.: New York, 1975; J.March, Advanced Organic Chemistry, Reactions, Mechanisms and Structure,(2^(nd) Ed.), McGraw Hill: New York, 1977; F. Carey and R. Sundberg,Advanced Organic Chemistry, Part B: Reactions and Synthesis, (2^(nd)Ed.), Plenum: New York, 1977; and references cited therein.

The term heteroalkyl refers to an alkyl group that contains a heteroatomin the alkyl chain, including O, S, N, or P, and wherein the heteroatomcan be attached to other substituents to complete the valence.Non-limiting examples of heteralkyl moieties include polyoxyalkylene,and when divalent, —(CH₂O)— wherein n is an integer of from 0 to 20.

The term heterocycle or heterocyclic, as used herein except where notedrepresents a stable 5- to 7-membered monocyclic or stable 8- to11-membered bicyclic heterocyclic ring which is either saturated orunsaturated, and which consists of carbon atoms and from one to threeheteroatoms selected from the group consisting of N, O and S; andwherein the nitrogen and sulfur heteroatoms may optionally be oxidized,and the nitrogen heteroatom may optionally be quaternized, and includingany bicyclic group in which any of the above-defined heterocyclic ringsis fused to a benzene ring. The heterocyclic ring may be attached at anyheteroatom or carbon atom which results in the creation of a stablestructure.

The term heteroaryl or heteroaromatic, as used herein, refers to anaromatic moiety that includes at least one sulfur, oxygen, nitrogen orphosphorus in the aromatic ring. The term heterocyclic refers to anonaromatic cyclic group wherein there is at least one heteroatom, suchas oxygen, sulfur, nitrogen, or phosphorus in the ring. Non-limitingexamples of heteroaryl and heterocyclic groups include furyl, furanyl,pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl,pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl,benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl,benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl,1,2,4-thiadiazolyl, isooxazolyl, pyrrolyl, quinazolinyl, cinnolinyl,phthalazinyl, xanthinyl, hypoxanthinyl, thiophene, furan, pyrrole,isopyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole,oxazole, isoxazole, thiazole, isothiazole, pyrimidine or pyridazine, andpteridinyl, aziridines, thiazole, isothiazole, 1,2,3-oxadiazole,thiazine, pyridine, pyrazine, piperazine, pyrrolidine, oxaziranes,phenazine, phenothiazine, morpholinyl, pyrazolyl, pyridazinyl,pyrazinyl, quinoxalinyl, xanthinyl, hypoxanthinyl, pteridinyl,5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl,pyrrolopyrimidinyl, pyrazolopyrimidinyl, adenine, N⁶-alkylpurines,N⁶-benzylpurine, N⁶-halopurine, N⁶-vinypurine, N⁶-acetylenic purine,N⁶-acyl purine, N⁶-hydroxyalkyl purine, N⁶-thioalkyl purine, thymine,cytosine, 6-azapyrimidine, 2-mercaptopyrmidine, uracil,N⁵-alkyl-pyrimidines, N⁵-benzylpyrimidines, N⁵-halopyrimidines,N⁵-vinyl-pyrimidine, N⁵-acetylenic pyrimidine, N⁵-acyl pyrimidine,N⁵-hydroxyalkyl purine, and N⁶-thioalkyl purine, and isoxazolyl. Theheteroaromatic and heterocyclic moieties can be optionally substitutedas described above for aryl, including substituted with one or moresubstituent selected from halogen, haloalkyl, alkyl, alkoxy, hydroxy,carboxyl derivatives, amido, amino, alkylamino, dialkylamino. Theheteroaromatic can be partially or totally hydrogenated as desired. As anonlimiting example, dihydropyridine can be used in place of pyridine.Functional oxygen and nitrogen groups on the heteroaryl group can beprotected as necessary or desired. Suitable protecting groups are wellknown to those skilled in the art, and include trimethylsilyl,dimethylhexylsilyl, t-butyldi-methylsilyl, and t-butyldiphenylsilyl,trityl or substituted trityl, alkyl groups, acyl groups such as acetyland propionyl, methanesulfonyl, and p-toluenesulfonyl.

As used herein, the terms “substantially free of” and “substantially inthe absence of” refer to a composition that includes at least 85-90% byweight, preferably 95%-98% by weight, and even more preferably 99%400%by weight, of the designated enantiomer of that compound. In a preferredembodiment, the compounds listed in the methods and compounds of thisinvention are substantially free of enantiomers other than for the onedesignated.

Similarly, the term “isolated” refers to a composition that includes atleast 85%-90% by weight, preferably 95%-98% by weight, and even morepreferably 99%-100% by weight, of the compound, the remainder comprisingother chemical species or enantiomers.

The term “independently” is used herein to indicate that a variable isapplied in any one instance without regard to the presence or absence ofa variable having that same or a different definition within the samecompound. Thus, in a compound in which R″ appears twice and is definedas “independently carbon or nitrogen”, both R″s can be carbon, both R″scan be nitrogen, or one R″ can be carbon and the other nitrogen.

The term “host”, as used herein, refers to unicellular or multicellularorganism in which abnormal cellular proliferation can be mimicked. Theterm host specifically refers to cells that abnormally proliferate,either from natural or unnatural causes (for example, from geneticmutation or genetic engineering, respectively), and animals, inparticular, primates (including chimpanzees) and humans. In most animalapplications of the present invention, the host is a human patient.Veterinary applications, in certain indications, however, are clearlyanticipated by the present invention.

III. Prodrugs and Derivatives

The active compound can be administered as any salt or prodrug that uponadministration to the recipient is capable of providing directly orindirectly the parent compound, or that exhibits activity itself.

A. Pharmaceutically Acceptable Salts

In cases where compounds are sufficiently basic or acidic to form stablenontoxic acid or base salts, administration of the compound as apharmaceutically acceptable salt may be appropriate.

The term “pharmaceutically acceptable salt” refers to a salt or complexof the active compound in which the compound carries a counterion thatis pharmaceutically acceptable and retains the desired biologicalactivity of the parent compound and exhibits minimal, if any, undesiredtoxicological effects. Any salt that retains the desired biologicalactivity of the compounds contained herein and that exhibits minimal orno undesired or toxicological effects is intended for inclusion here.

Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid affording aphysiologically acceptable anion. Alkali metal (for example, sodium,potassium or lithium) or alkaline earth metal (for example calcium)salts of carboxylic acids can also be made.

Nonlimiting examples of such salts are (a) acid addition salts formedwith inorganic acids (for example, hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, nitric acid, bicarbonic acid, carbonicacid and the like), and salts formed with organic acids such as aceticacid, oxalic acid, formic acid, fumaric acid, propionic acid, glycolicacid, lactic acid, pyruvic acid, maleic acid, salicylic acid, tartaricacid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannicacid, palmoic acid, alginic acid, polyglutamic acid, tosic acid,methanesulphonic acid, citric acid, malonic acid, α-ketoglutaric acid,α-glycerophosphonic acid, naphthalenesulfonic acids,naphthalene-disulfonic acids, and polygalacturonic acid; (b) baseaddition salts formed with cations such as sodium, potassium, lithium,zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt,nickel, cadmium, and the like, or with an organic cation, for example,formed from an amine, such as ammonium, N,N-dibenzyl-ethylenediamine,D-glucosamine, tetraethylammonium, or ethylenediamine; or (c)combinations of (a) and (b), e.g., a zinc tannate salt or the like.

B. Prodrugs

Any of the compounds described herein can be administered as a prodrugto increase the activity, bioavailability, stability or otherwise alterthe properties of the compound. A pharmaceutically acceptable prodrugrefers to a compound that is metabolized (i.e., hydrolyzed or oxidized,for example) in the host to form a compound of the present invention.Typical examples of prodrugs include compounds that have biologicallylabile protecting groups on a functional moiety of the active compound.Prodrugs include compounds that can be oxidized, reduced, aminated,deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed,alkylated, dealkylated, acylated, deacylated, phosphorylated, and/ordephosphorylated to produce the active compound. The compounds of thisinvention possess anti-proliferative activity against abnormallyproliferating cells, or are metabolized to a compound that exhibits suchactivity.

A number of prodrug ligands are known. In general, alkylation, acylationor other lipophilic modification of one or more heteroatoms of thecompound, such as a free amine or carboxylic acid residue, reducespolarity and allows passage into cells. Examples of substituent groupsthat can replace one or more hydrogens on the free amine and/orcarboxylic acid moiety are alkyl, aryl, steroids, carbohydrates,including sugars, 1,2-diacylglycerol, alcohols, acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asprovided in the definition of an aryl given herein; optionallysubstituted arylsulfonyl; a lipid, including a phospholipid;phosphotidylcholine, phosphocholine, an amino acid residue orderivative; an amino acid acyl residue or derivative; a carbohydrate; apeptide; cholesterol; or other pharmaceutically acceptable leaving groupwhich, when administered in vivo, provides the free amine and/orcarboxylic acid moiety. Any of these can be used in combination with thedisclosed compounds to achieve a desired effect.

C. Stereochemistry

It is to be understood that the compounds disclosed herein may containchiral centers. Such chiral centers may be of either the (R) or (S)configuration, or may be a mixture thereof. Thus, the compounds providedherein may be enantiomeric ally pure, or be stereoisomeric ordiastereomeric mixtures. It is understood that the disclosure of acompound herein encompasses any racemic, optically active, polymorphic,or steroisomeric form, or mixtures thereof, which preferably possessesthe useful properties described herein, it being well known in the arthow to prepare optically active forms and how to determine activityusing the standard tests described herein, or using other similar testswhich are will known in the art. Examples of methods that can be used toobtain optical isomers of the compounds include the following:

i) physical separation of crystals—a technique whereby macroscopiccrystals of the individual enantiomers are manually separated. Thistechnique can be used if crystals of the separate enantiomers exist,i.e., the material is a conglomerate, and the crystals are visuallydistinct;

ii) simultaneous crystallization—a technique whereby the individualenantiomers are separately crystallized from a solution of the racemate,possible only if the latter is a conglomerate in the solid state;

iii) enzymatic resolutions—a technique whereby partial or completeseparation of a racemate by virtue of differing rates of reaction forthe enantiomers with an enzyme

iv) enzymatic asymmetric synthesis, a synthetic technique whereby atleast one step of the synthesis uses an enzymatic reaction to obtain anenantiomerically pure or enriched synthetic precursor of the desiredenantiomer;

v) chemical asymmetric synthesis—a synthetic technique whereby thedesired enantiomer is synthesized from an achiral precursor underconditions that produce asymetry (i.e., chirality) in the product, whichmay be achieved using chiral catalysts or chiral auxiliaries;

vi) diastereomer separations—a technique whereby a racemic compound isreacted with an enantiomerically pure reagent (the chiral auxiliary)that converts the individual enantiomers to diastereomers. The resultingdiastereomers are then separated by chromatography or crystallization byvirtue of their now more distinct structural differences and the chiralauxiliary later removed to obtain the desired enantiomer;

vii) first- and second-order asymmetric transformations a techniquewhereby diastereomers from the racemate equilibrate to yield apreponderance in solution of the diastereomer from the desiredenantiomer or where preferential crystallization of the diastereomerfrom the desired enantiomer perturbs the equilibrium such thateventually in principle all the material is converted to the crystallinediastereomer from the desired enantiomer. The desired enantiomer is thenreleased from the diastereomer;

viii) kinetic resolutions—this technique refers to the achievement ofpartial or complete resolution of a racemate (or of a further resolutionof a partially resolved compound) by virtue of unequal reaction rates ofthe enantiomers with a chiral, non-racemic reagent or catalyst underkinetic conditions;

ix) enantiospecific synthesis from non-racemic precursors—a synthetictechnique whereby the desired enantiomer is obtained from non-chiralstarting materials and where the stereochemical integrity is not or isonly minimally compromised over the course of the synthesis;

x) chiral liquid chromatography, a technique whereby the enantiomers ofa racemate are separated in a liquid mobile phase by virtue of theirdiffering interactions with a stationary phase. The stationary phase canbe made of chiral material or the mobile phase can contain an additionalchiral material to provoke the differing interactions;

xi) chiral gas chromatography, a technique whereby the racemate isvolatilized and enantiomers are separated by virtue of their differinginteractions in the gaseous mobile phase with a column containing afixed non-racemic chiral adsorbent phase;

xii) extraction with chiral solvents—a technique whereby the enantiomersare separated by virtue of preferential dissolution of one enantiomerinto a particular chiral solvent; and

xiii) transport across chiral membranes—a technique whereby a racemateis placed in contact with a thin membrane barrier. The barrier typicallyseparates two miscible fluids, one containing the racemate, and adriving force such as concentration or pressure differential causespreferential transport across the membrane barrier. Separation occurs asa result of the non-racemic chiral nature of the membrane which allowsonly one enantiomer of the racemate to pass through.

The compound optionally may be provided in a composition that isenantiomerically enriched, e.g., a mixture of enantiomers in which oneenantiomer is present in excess, e.g., to the extent of 95% or more, or98% or more, including 100%.

IV. Synthesis

As depicted in FIG. 2, the process of the invention for the synthesis ofa sub-embodiment of the compound of Formula (I) starts with theconversion of commercially available 5-methyl-2-nitrobenzoic acid to thecorresponding amide (2) and its subsequent transformation to5-methyl-2-nitrobenzonitrile (3) by standard procedures. Reaction of (3)in DMF under nitrogen with p-formylmethylbenzoate in the presence of anorganic base such as diazabicylo octane for several hours gave theolefin (4) after work up as a mixture of geometric isomers. Olefin (4)can also be prepared by reacting (3) with p-formylmethylbenzoate inmethanol using sodium methoxide as a base. In general, this reaction canbe performed in any appropriate organic solvent using commonly usedorganic or inorganic bases. Reduction of (4) with a reducing agent, suchas sodium dithionite, gave the aminonitrile (5), which was cyclized withguanidine to the corresponding pteroate analogue (6), which aftercatalytic hydrogenation and hydrolysis gave4-amino-4-deoxy-5,8,10-trideazapteroic acid (7). Coupling of (7) withdiethyl-4-methyleneglutamate by the isobutylchlorformate methodpreviously described by Nair and Baugh [Biochemistry (1973) 12:3923-3927] followed by mild hydrolysis of the resultant diester gavecrude (1) which was purified by reverse phase chromatography on C-18silica gel using 12% acetonitrile in water as the eluting solvent[Scheme-1].

An alternate procedure for the preparation of olefine (4) is allylicbromination of (3) to the corresponding benzyl bromide (3b), and itssubsequent reaction with triphenylphosphine to the Wittig salt.Treatment of this Wittig salt with p-formylmethylbenzoate in an organicsolvent (e.g., DMF) using an organic base in a typical Wittig reactiongave (4) in moderate yield. Any convenient organic solvent and anorganic or inorganic base compatible with the solvent can be used forthis reaction.

Substitution of p-formyl methylbenzoate with p-carbomethoxyacetophenonein the above reaction with (3) gives the corresponding methylsubstituted olefin which after dithionite reduction, guanidinecyclization, hydrogenation, hydrolysis, diethyl-4-methyleneglutamatecoupling followed by hydrolysis yields the 10-methyl derivative (1a).Likewise, substitution of p-formyl methylbenzoate withp-carbomethoxy-propiophenone in the reaction with (3) and workup asabove should yield the 10-ethyl derivative (1b).

Benzylic bromination of (3) gave the corresponding bromomethylderivative (3b) that on reaction with p-methylaminomethybenzoate andmethyl-p-methylaminobenzoate gave the corresponding aminonitriles whichafter dithionite reduction, guanidine cyclization and hydrolysis gavethe pteroate analogs (3) and (9). 4-Methyleneglutamate couplingdescribed as above and hydrolysis gave the 10-nor-methylamino and10-nor-amino derivatives (1c) and (1d), respectively.

V. Pharmaceutical Compositions and Administration

Any host organism, including a patient, mammal, and specifically ahuman, suffering from any of the above-described conditions can betreated by the administration of a composition comprising an effectiveamount of the compound of formula (I) or formula (II) or apharmaceutically acceptable salt, prodrug or ester thereof, optionallyin a pharmaceutically acceptable carrier. The term “carrier” includesbut is not limited to diluents, binders, lubricants, disintegrators,fillers, and coating compositions.

An effective dose for any of the herein described conditions can bereadily determined by the use of conventional techniques and byobserving results obtained under analogous circumstances. In determiningthe effective dose, a number of factors are considered including, butnot limited to: the species of patient; its size, age, and generalhealth; the specific disease involved; the degree of involvement or theseverity of the disease; the response of the individual patient; theparticular compound administered; the mode of administration; thebioavailability characteristics of the preparation administered; thedose regimen selected; and the use of concomitant medication. Thecompound is administered for a sufficient time period to alleviate theundesired symptoms and the clinical signs associated with the conditionbeing treated.

The active compound is included in the pharmaceutically acceptablecarrier or diluent in an amount sufficient to deliver to a patient atherapeutic amount of compound in vivo in the absence of serious toxiceffects. The concentration of active compound in the drug compositionwill depend on absorption, inactivation, and excretion rates of the drugas well as other factors known to those of skill in the art. It is to benoted that dosage values will also vary with the severity of thecondition to be alleviated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions, and that the dosage ranges set forth herein are exemplaryonly and are not intended to limit the scope or practice of the claimedcomposition. The active ingredient may be administered at once, or maybe divided into a number of smaller doses to be administered at varyingintervals of time.

The compound can also be mixed with other active materials that do notimpair the desired action, or with materials that supplement the desiredaction. For a detailed description, see, for example, Section VII,“Combination Therapies.”

The formulations of the pharmaceutical compositions described herein maybe prepared by any method known or hereafter developed in the art ofpharmacology. In general, such preparatory methods include the step ofbringing the therapeutic compound into association with a carrier or oneor more other accessory ingredients, and then, if necessary ordesirable, shaping or packaging the product into a desired single- ormulti-dose unit.

In one embodiment, compound may be administered orally in combinationwith a pharmaceutically acceptable vehicle such as an inert diluent oran edible carrier. Oral compositions may be enclosed in hard or softshell gelatin capsules, may be compressed into tablets or may beincorporated directly with the food of the patient's diet. For thepurpose of oral therapeutic administration, the compound can beincorporated with one or more excipients and used in the form oftablets, buccal tablets, troches, capsules, elixirs, suspensions,syrups, wafers and the like. The percentage of the composition andpreparations may be varied, and may conveniently be between from about2% to about 60% of the weight of a given unit dosage form. The amount ofsubstance in such therapeutically useful compositions is such that aneffective dosage level will be obtained.

The tablets, pills, capsules, troches and the like can contain any ofthe following ingredients, or compounds of a similar nature: a bindersuch as microcrystalline cellulose, gum tragacanth or gelatin; anexcipient such as starch or lactose, a disintegrating agent such asalginic acid, Primogel, or corn starch; a lubricant such as magnesiumstearate or Sterotes; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring. In one particularembodiment, the compounds and compositions disclosed herein can beformulated as microcrystalline cellulose tablets.

Hard capsules containing the compound may be made using aphysiologically degradable composition, such as gelatin. Such hardcapsules comprise the compound, and may further comprise additionalingredients including, for example, an inert solid diluent such ascalcium carbonate, calcium phosphate, or kaolin. Soft gelatin capsulescontaining the compound may be made using a physiologically degradablecomposition, such as gelatin. Such soft capsules comprise the compound,which may be mixed with water or an oil medium such as peanut oil,liquid paraffin, or olive oil.

Sublingual tablets are designed to dissolve very rapidly. Examples ofsuch formulations include ergotamine tartrate, isosorbide dinitrate,isoproterenol HCL. The formulations of these tablets contain, inaddition to the drug, a limited number of soluble excipients, usuallylactose and powdered sucrose, but sometimes dextrose and mannitol.

The solid dosage forms of the present invention may optionally becoated. Examples of suitable coating materials include, but are notlimited to, cellulose polymers such as cellulose acetate phthalate,hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropylmethylcellulose phthalate and hydroxypropyl methylcellulose acetatesuccinate; polyvinyl acetate phthalate, acrylic acid polymers andcopolymers, and methacrylic resins that are commercially available underthe trade name Eudragit® (Roth Pharma, Westerstadt, Germany), Zein,shellac, and polysaccharides.

Powdered and granular formulations of a pharmaceutical preparation ofthe invention may be prepared using known methods. Such formulations maybe administered directly to a patient used, for example, to formtablets, to fill capsules, or to prepare an aqueous or oily suspensionor solution by addition of an aqueous or oily vehicle thereto. Each ofthese formulations may further comprise one or more of dispersing orwetting agent, a suspending agent, and a preservative. Additionalexcipients (e.g., fillers and sweetening, flavoring, or coloring agents)may also be included in these formulations.

Liquid formulations of the pharmaceutical composition of the inventionwhich are suitable for oral administration may be prepared, packaged,and sold either in liquid form or in the form of a dry product intendedfor reconstitution with water or another suitable vehicle prior to use.

Liquid suspensions may be prepared using conventional methods to achievesuspension of the compound and an aqueous or oily vehicle. Aqueousvehicles include, for example, water and isotonic saline. Oily vehiclesinclude, for example, almond oil, oily esters, ethyl alcohol, vegetableoils such as arachis, olive, sesame, or coconut oil, fractionatedvegetable oils, and mineral oils such as liquid paraffin. Liquidsuspensions may also contain one or more additional ingredientsincluding, but not limited to, suspending agents, dispersing or wettingagents, emulsifying agents, demulcents, preservatives, buffers, salts,flavorings, coloring agents, and sweetening agents. Oily suspensions mayfurther comprise a thickening agent. Suspending agents may include, forexample, sorbitol syrup, hydrogenated edible fats, sodium alginate,polyvinylpyrrolidone, gum tragacanth, gum acacia, and cellulosederivatives such as sodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose. Dispersing or wetting agents may include,for example, naturally-occurring phosphatides such as lecithin,condensation products of an alkylene oxide with a fatty acid, with along chain aliphatic alcohol, with a partial ester derived from a fattyacid and a hexitol, or with a partial ester derived from a fatty acidand a hexitol anhydride (e.g., polyoxyethylene stearate,heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, andpolyoxyethylene sorbitan monooleate, respectively). Emulsifying agentsinclude, but are not limited to, lecithin and acacia. Preservatives mayinclude, for example, methyl, ethyl, or n-propyl-para-hydroxybenzoates,ascorbic acid, and sorbic acid. Sweetening agents include, for example,glycerol, propylene glycol, sorbitol, sucrose, and saccharin. Thickeningagents for oily suspensions include, for example, beeswax, hardparaffin, and acetyl alcohol.

Liquid solutions of the active ingredient in aqueous or oily solventsmay be prepared in substantially the same manner as liquid suspensions,wherein the active ingredient is dissolved, rather than suspended in thesolvent. Liquid solutions of the pharmaceutical composition of theinvention may contain each of the components described above for liquidsuspensions, other than suspending agents, which are unnecessary.Aqueous solvents include, for example, water and isotonic saline. Oilysolvents include, for example, almond oil, oily esters, ethyl alcohol,vegetable oils such as arachis, olive, sesame, or coconut oil,fractionated vegetable oils, and mineral oils such as liquid paraffin.

Administration

The compositions can be administered in any desired manner, including,but not limited to, oral, topical, parenteral, intravenous, intradermal,intra-articular, intra-synovial, intrathecal, intra-arterial,intracardiac, intramuscular, subcutaneous, intraorbital, intracapsular,intraspinal, intrastemal, topical, transdermal patch, via rectal,vaginal or urethral suppository, peritoneal, percutaneous, nasal spray,surgical implant, internal surgical paint, infusion pump, or viacatheter, stent, balloon or other delivery device.

Parenteral administration of the pharmaceutical composition includes anyroute of administration characterized by physical breaching of a tissueof a subject and administration of the pharmaceutical compositionthrough the breach in the tissue, such as administration of thepharmaceutical composition by injection of the composition, byapplication of the composition through a surgical incision, byapplication of the composition through a tissue-penetrating non-surgicalwound, and the like.

Formulations of a pharmaceutical composition suitable for parenteraladministration comprise the compound combined with a pharmaceuticallyacceptable carrier, such as sterile water or sterile isotonic saline.Formulations suitable for parenteral administration include, forexample, suspensions, solutions, emulsions in oily or aqueous vehicles.Such formulations may further comprise one or more additionalingredients including, but not limited to, suspending, stabilizing, ordispersing agents. In one embodiment of a formulation for parenteraladministration, the compound is provided in dry (i.e., powder orgranular) form for reconstitution with a suitable vehicle (e.g., sterilepyrogen-free water) prior to parenteral administration of thereconstituted composition.

In one embodiment, the compound administered intravenously orintraperitoneally by infusion or injection. The pharmaceutical dosageforms suitable for infusion or injection can include sterile aqueoussolutions or dispersions or sterile powders containing the substancewhich are adapted for the extemporaneous preparation of sterileinjectable or infusible solutions or dispersions, optionallyencapsulated in liposomes. In all cases, the ultimate dosage form mustbe sterile, fluid and stable under the conditions of storage ormanufacture. The liquid carrier or vehicle can be a solvent or liquiddispersion medium comprising, for example, water, normal saline,ethanol, a polyol (e.g.; glycerol, propylene glycol, liquid polyethyleneglycol and the like), vegetable oils, nontoxic glyceryl esters, andsuitable mixtures thereof. The proper fluidity can be maintained, forexample, by the formation of liposomes, by the maintenance of therequired particle size in the case of dispersions or by the use ofsurfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, benzyl alcohol, sorbic acid,thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the substancein the required amount in the appropriate solvent with various of theother ingredients enumerated above, as required, followed by filtersterilization. In the case of sterile powders for the preparation ofsterile injectable solutions, the preferred methods of preparation arevacuum drying and the freeze drying techniques, which yield a powder ofthe active ingredient plus any additional desired ingredient present inthe previously sterile-filtered solutions.

Injectable solutions are particularly advantageous for localadministration of the therapeutic composition. In particular,parenchymal injection can be used to deliver the therapeutic compositiondirectly to a tumorous growth. Intra-articular injection is a preferredalternative in cases of arthritis where the practitioner wishes to treatone or only a few (such as 2-6) joints. Additionally, the therapeuticcompounds are injected directly into lesions (intra-lesionadministration) in appropriate cases. Intradermal administration is analternative for dermal lesions.

The compounds of the present invention are optionally administeredtopically. Formulations suitable for topical administration include, forexample, liniments, lotions, oil-in-water or water-in-oil emulsions suchas creams, ointments or pastes, and solutions or suspensions. Ointmentsare semisolid preparations which are typically based on petrolatum orother petroleum derivatives. Creams containing the compound aretypically viscous liquid or semisolid emulsions, often eitheroil-in-water or water-in-oil. Cream bases are typically water-washable,and contain an oil phase, an emulsifier and an aqueous phase. The oilphase, also sometimes called the “internal” phase, is generallycomprised of petrolatum and a fatty alcohol such as cetyl or stearylalcohol; the aqueous phase usually, although not necessarily, exceedsthe oil phase in volume, and generally contains a humectant. Theemulsifier in a cream formulation is generally a nonionic, anionic,cationic or amphoteric surfactant. The specific ointment or cream baseto be used, as will be appreciated by those skilled in the art, is onethat will provide for optimum drug delivery. As with other carriers orvehicles, an ointment base should be inert, stable, nonirritating andnonsensitizing. Formulations for topical administration may furthercomprise one or more of the additional ingredients described herein.

In one embodiment, the compound is delivered through the skin usingtransdermal drug delivery system. In a specific embodiment, the activeingredient is contained within a laminated structure that serves as adrug delivery device to be affixed to the skin- e.g. a patch. In such astructure, the drug composition is typically contained in a layer, or“reservoir,” underlying an upper backing layer. The patch may contain asingle reservoir, or it may contain multiple reservoirs.

In one particular embodiment of the present invention, the, compoundsand/or compositions described herein can be administered topically forthe treatment of a abnormal cell proliferation disorder. In oneembodiment, the disorder can be psoriasis. In another particularembodiment, the compounds and/or compositions described herein can beadministered topically, for example, as a cream, for the treatment ofpsoriasis.

For pulmonary delivery, the compound may be administered to the lungs ofa subject by any suitable means, but are preferably administered byadministering an aerosol suspension of respirable particles comprised ofthe active compound, which the subject inhales. The respirable particlesmay be liquid or solid. The active compound can be aerosolized in avariety of forms, such as, but not limited to, dry powder inhalants,metered dose inhalants, or liquid/liquid suspensions.

In one embodiment, the formulation may contain the compound in the formof dry particles. Such compositions are conveniently in the form of drypowders for administration using a device comprising a dry powderreservoir to which a stream of propellant may be directed to dispersethe powder or using a self-propelling solvent/powder-dispensingcontainer such as a device comprising the compound dissolved orsuspended in a low-boiling propellant in a sealed container. Dry powdercompositions preferably include a solid fine powder diluent such assugar and are conveniently provided in a unit dose form.

In one embodiment, the formulation for pulmonary delivery provides thecompound in the form of droplets of a solution or suspension. Suchformulations may be prepared, packaged, or sold as aqueous or dilutealcoholic solutions or suspensions, optionally sterile, comprising theactive ingredient, and may conveniently be administered using anynebulization or atomization device. Such formulations may furthercomprise one or more additional ingredients including, for example, aflavoring agent such as saccharin sodium, a volatile oil, a bufferingagent, a surface active agent, or a preservative such asmethylhydroxybenzoate.

Aerosols of solid particles containing the active compound may beproduced with any solid particulate medicament aerosol generator.Aerosol generators suitable for administering solid particulatemedicaments to a subject produce particles which are respirable andgenerate a volume of aerosol containing a predetermined metered dose ofa medicament at a rate suitable for human administration. Arepresentative solid particulate aerosol generator is an insufflator.Suitable formulations for administration by insufflation include finelycomminuted powders which may be delivered by means of an insufflator ortaken into the nasal cavity in the manner of a snuff. In theinsufflator, the powder (e.g., a metered dose thereof effective to carryout the treatments described herein) is contained in capsules orcartridges, typically made of gelatin or plastic, which are eitherpierced or opened in situ and the powder delivered by air drawn throughthe device upon inhalation or by means of a manually-operated pump. Thepowder employed in the insufflator consists either solely of the activeingredient or of a powder blend comprising the active ingredient, asuitable powder diluent, such as lactose, and an optional surfactant.The active ingredient typically comprises from 0.1 to 100 w/w of theformulation.

The metered dose inhaler provides a second example of a solidparticulate aerosol generator. Metered dose inhalers are pressurizedaerosol dispensers, which typically contain a suspension or solutionformulation of the active ingredient in a liquified propellant. Duringuse these devices discharge the formulation through a valve adapted todeliver a metered volume, typically from 10 to 200 μL, to produce a fineparticle spray containing the active ingredient. Suitable propellantsinclude, for example, chlorofluorocarbon compounds (e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane and mixtures thereof). The formulation mayadditionally contain one or more co-solvents, for example, ethanol,surfactants, such as oleic acid or sorbitan trioleate, antioxidants andsuitable flavoring agents.

Aerosols of liquid particles comprising the active compound may beproduced by any suitable means, such as with a pressure-driven jetaerosol nebulizer or an ultrasonic nebulizer. See, e.g., U.S. Pat. No.4,501,729. Nebulizers transform solutions or suspensions of the activeingredient into a therapeutic aerosol mist either by means ofacceleration of compressed gas, typically air or oxygen, through anarrow venturi orifice or by means of ultrasonic agitation. Suitableformulations for use in nebulizers consist of the active ingredient in aliquid carrier, the active ingredient comprising up to 40% w/w of theformulation, but preferably less than 20% w/w.

Solid or liquid particulate pharmaceutical formulations should includeparticles sizes should be within a range suitable for depositing atherapeutically effective amount in the lungs or in the airways, e.g.,about 1-10 microns, to treat the lung condition of a patient in need ofsuch treatment. Particles greater in size which are included in theaerosol tend to be deposited in the throat and swallowed, and thequantity of non-respirable particles in the aerosol is preferablyminimized.

The formulations described herein as being useful for pulmonary deliveryare also useful for intranasal delivery of a pharmaceutical compositionof the invention. For nasal administration, a particle size in the rangeof 10-500 microns is preferred to ensure retention in the nasal cavity.

For ophthalmic applications, the therapeutic compound is formulated intosolutions, suspensions, and ointments appropriate for use in the eye.For opthalmic formulations, see Mitra (ed.), Ophthalmic Drug DeliverySystems, Marcel Dekker, Inc., New York, N.Y. (1993), and also Havener,W. H., Ocular Pharmacology, C. V. Mosby Co., St. Louis (1983).

In one embodiment of the present invention, the compounds are preparedwith carriers that will protect the compound against rapid eliminationfrom the body, such as controlled release formulations. Controlledrelease formulations include, for example, delayed release or extendedrelease formulations. The controlled-release of the compound can becontrolled in any way suitable for achieving the desired result. Booksdescribing methods of controlled delivery that are appropriate for thedelivery of 4-PBA include: Robert S. Langer, Donald L. Wise, editors;Medical applications of controlled release (Volumes 1 and 2); BocaRaton, Fla.: CRC Press, 1984; and William J. M. Hrushesky, Robert Langerand Felix Theeuwes, editors; Temporal control of drug delivery (series);New York: New York Academy of Sciences, 1991. Representative,non-limiting systems suitable for use in the present invention includediffusion controlled, solvent controlled and chemically controlledsystems.

Diffusion controlled systems suitable for use in the present inventioninclude systems involving (i) diffusion through a membrane; and (ii)diffusion through a bulk polymer. In a membrane system, otherwise knownas a reservoir device, diffusion of water through the polymer membraneis the rate determining step. Reservoir devices include oral,implantable or transdermal systems, for example. In one embodiment ofthe present invention, the active ingredient is encapsulated within apolymer film or coat. Representative, non-limiting polymers includecellulose ester, cellulose ether, an acrylic polymer, or a mixture ofpolymers.

In one embodiment of the present invention, sustained release of thecompound is achieved through microencapsulation. Microcapsules aredefined as microparticles having an outer polymer shell surrounding acore of another material, in this case, the compound of the presentinvention. The size of a microcapsule can vary from just a few micronsto several millimeters. The microencapsulation drug delivery system mayutilize any of a number of protective wall or covering materials,including proteins, polysaccharides, starches, waxes, fats, polymers andresins.

In one embodiment of the present invention, controlled release of thecompound is achieved using a monolithic (matrix) device. Release is bycontinuous leaching of the drug from the polymer matrix core. Monolithicdevice may be formed, for example, by the compression of thepolymer/drug mixture or by dissolution or melting. One type of matrixformulation is a matrix tablet, which is a matrix formulation in tabletform. The rate of release through the bulk polymer depends upon theamount of drug present at a particular time, and is therefore timedependent.

The three major types of materials suitable for use in the preparationof matrix devices include (i) insoluble plastics; (ii) hydrophilicpolymers; and (iii) fatty compounds. Plastic matrixes are chemicallyinert and have a good drug embedding ability. Examples of suitablethermoplastic polymers are those having formulas incorporating monomericunits such as lactides, glycolides, caprolactones, anhydrides, amides,urethanes, esteramides, orthoesters, dioxanones, acetals, ketals,carbonates, phosphazenes, hydroxybutyrates, hydroxyvalerates, alkyleneoxalates, alkylene succinates, and amino acids. Copolymers of anycombination of lactide, caprolactone, and glycolide monomeric units arepreferred.

Representative hydrophilic polymers suitable for use in a polymer matrixinclude cellulose derivatives, noncellulose polysaccharides,polyethylene oxide, polyvinyl alcohols and acrylic acid copolymers.Representative, non-limiting examples of cellulose derivatives includemethylcellulose, hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose, hydroxypropyl cellulose, carboxymethylcellulose,hydroxomethylcellulose, hemicellulose, and methylcellulose.

Fatty compounds include, but are not limited to, fatty excipientsincluding glycerides (e.g., mono-, di- or triglycerides such as stearin,palnitin, laurin, myristin, hydrogenated castor or cottonseed oils,precirol), fatty acids and alcohols (e.g., stearic, palmitic or lauricacids; stearyl, cetyl or cetostearyl alcohols), fatty acid esters (e.g.,monostearates of propylene glycol and of sucrose, sucrose distearate)and waxes (e.g., white wax, cachalot wax).

The matrix may include a single polymer type or multiple polymer types(i.e., a polymer blend). Representative U.S. patent disclosing polymerblends include U.S. Pat. No. 5,128,143 (Baichwal et al.) entitled“Sustained Release Excipient and Tablet Formation”; U.S. Pat. No.4,842,866 (Horder et al) entitled “Slow Release Solid Preparation”; U.S.Pat. No. 5,811,126 (Krishnamurthy) entitled “Controlled Release Matrixfor Pharmaceuticals”; U.S. Pat. No. 3,965,256 (Leslie) entitled “SlowRelease Pharmaceutical Composition”; and U.S. Pat. No. 4,235,870(Leslie) entitled “Slow Release Pharmaceutical Compositions.” In apolymer blend, the ratio of the two polymer types may be equal ordifferent. A representative, non-limiting example of a hydrophilicpolymer blend is a polyvinyl alcohol (PVA) and polyvinyl pyrrolidone(PVP)-based matrix.

The devices with different drug release mechanisms described above couldbe combined in a final dosage form comprising single or multiple units.Examples of multiple units include multilayer tablets, capsulescontaining tablets, beads, granules, etc.

Osmotically controlled systems are also suitable for use in the presentinvention. The osmotic pump is one such system. It is similar to areservoir device but contains an osmotic agent (e.g., the active agentin salt form) which acts to imbibe water from the surrounding medium viaa semi-permeable membrane. See Theeuwes F., Elementary Osmotic Pump., J.Pharm. Sci., 64 (12), 1987-1991, 1975.

Chemically controlled systems are also suitable for use in the presentinvention. Chemically controlled systems include (i) erosion basedsystems; and (ii) pendant systems (i.e., combination of hydrolysis ofpendant group and diffusion from bulk polymer). One type of erosionbased system is a biodegradable polymer-based system. Representative,non-limiting examples of biodegradable polymers include naturallyoccurring biodegradable polymers such as alginate, dextrin, cellulose,collagen, chitosan; chemically or enzymatrically modified naturallyoccurring biodegradable polymers; and synthetic biodegradable polymers,such as polyanhydrides, polyesters, polyacrylic acids polyurethanes,polyphosphoesters and polyphosphazenes and poly(methyl methacrylates.

Non-limiting examples of U.S. Patents that describe controlled releaseformulations are: U.S. Pat. No. 5,356,630 to Laurencin et al. (DeliverySystem for Controlled Release of Bioactive Factors); U.S. Pat. No.5,797,898 to Santini, Jr. et al. (Microchip Drug Delivery Devices); U.S.Pat. No. 5,874,064 to Edwards et al. (Aerodynamically Light Particlesfor Pulmonary Drug Delivery); U.S. Pat. No. 5,548,035 to Kim et al.(Biodegradable Copolymer as Drug Delivery Matrix ComprisingPolyethyleneoxide and Aliphatic Polyester Blocks); U.S. Pat. No.5,532,287 to Savage et al. (Radiation Cured Drug Release ControllingMembrane); U.S. Pat. No. 5,284,831 to Kahl et al. (Drug DeliveryPorphyrin Composition and Methods); U.S. Pat. No. 5,741,329 to Agrawalet al. (Methods of Controlling the pH in the Vicinity of BiodegradableImplants); U.S. Pat. No. 5,820,883 to Tice et al. (Methods forDelivering Bioactive Agents into and Through the Mucosally-AssociatedLymphoid Tissues and Controlling Their Release); U.S. Pat. No. 5,955,068to Gouin et al. (Biodegradable polyanhydrides Derived from Dimers ofBile Acids and Use Thereof as Controlled Drug Release Systems); U.S.Pat. No. 6,001,395 to Coombes et al. (Polymeric Lamellar SubstrateParticles for Drug Delivery); U.S. Pat. No. 6,013,853 to Athanasiou etal. (Continuous Release Polymeric Implant Carriers); U.S. Pat. No.6,060,582 to Hubbell et al. (Photopolymerizable Biodegradable Hydrogelsas Tissue Contacting Materials and Controlled Release Carriers); U.S.Pat. No. 6,113,943 to Okada et al. (Sustained-Release PreparationCapable of Releasing a Physiologically Active Substance); and PCTPublication No. WO 99/59548 to Oh et al. (Controlled Drug DeliverySystem Using the Conjugation of Drug to Biodegradable Polyester); U.S.Pat. No. 6,123,861 (Fabrication of Microchip Drug Delivery Devices);U.S. Pat. No. 6,060,082 (Polymerized Liposomes Targeted to M cells andUseful for Oral or Mucosal Drug Delivery); U.S. Pat. No. 6,041,253(Effect of Electric Field and Ultrasound for Transdermal Drug Delivery);U.S. Pat. No. 6,018,678 (Transdermal protein delivery or measurementusing low-frequency sonophoresis); U.S. Pat. No. 6,007,845 NanoparticlesAnd Microparticles Of Non-Linear Hydrophilic-Hydrophobic MultiblockCopolymers; U.S. Pat. No. 6,004,534 Targeted Polymerized Liposomes ForImproved Drug Delivery; U.S. Pat. No. 6,002,961 Transdermal ProteinDelivery Using Low-Frequency Sonophoresis; U.S. Pat. No. 5,985,309Preparation Of Particles For Inhalation; U.S. Pat. No. 5,947,921Chemical And Physical Enhancers And Ultrasound For Transdermal DrugDelivery; U.S. Pat. No. 5,912,017 Multiwall Polymeric Microspheres; U.S.Pat. No. 5,911,223 Introduction Of Modifying Agents Into Skin ByElectroporation; U.S. Pat. No. 5,874,064 Aerodynamically Light ParticlesFor Pulmonary Drug Delivery; U.S. Pat. No. 5,855,913 ParticlesIncorporating Surfactants For Pulmonary Drug Delivery; U.S. Pat. No.5,846,565 Controlled Local Delivery Of Chemotherapeutic Agents ForTreating Solid Tumors; U.S. Pat. No. 5,837,752 Semi-InterpenetratingPolymer Networks; U.S. Pat. No. 5,814,599 Transdermal Delivery OfEncapsulated Drugs; U.S. Pat. No. 5,804,178 Implantation Of Cell-MatrixStructure Adjacent Mesentery, Omentum Or Peritoneum Tissue; U.S. Pat.No. 5,797,898 Microchip Drug Delivery Devices; U.S. Pat. No. 5,770,417Three-Dimensional Fibrous Scaffold Containing Attached Cells ForProducing Vascularized Tissue In vivo; U.S. Pat. No. 5,770,193Preparation Of Three-Dimensional Fibrous Scaffold For Attaching Cells ToProduce Vascularized Tissue In vivo; U.S. Pat. No. 5,762,904 OralDelivery Of Vaccines Using Polymerized Liposomes; U.S. Pat. No.5,759,830 Three-Dimensional Fibrous Scaffold Containing Attached CellsFor Producing Vascularized Tissue In vivo; U.S. Pat. No. 5,749,847Delivery Of Nucleotides Into Organisms By Electroporation; U.S. Pat. No.5,736,372 Biodegradable Synthetic Polymeric Fibrous Matrix ContainingChondrocyte For In vivo Production Of A Cartilaginous Structure; U.S.Pat. No. 5,718,921 Microspheres Comprising Polymer And Drug DispersedThere Within; U.S. Pat. No. 5,696,175 Preparation Of Bonded FiberStructures For Cell Implantation; U.S. Pat. No. 5,667,491 Method ForRapid Temporal Control Of Molecular Transport Across Tissue; U.S. Pat.No. 5,654,381 Functionalized Polyester Graft Copolymers; U.S. Pat. No.5,651,986 Controlled Local Delivery Of Chemotherapeutic Agents ForTreating Solid Tumors; U.S. Pat. No. 5,629,009 Delivery System ForControlled Release Of Bioactive Factors; U.S. Pat. No. 5,626,862Controlled Local Delivery Of Chemotherapeutic Agents For Treating SolidTumors; U.S. Pat. No. 5,593,974 Localized Oligonucleotide Therapy; U.S.Pat. No. 5,578,325 Nanoparticles And Microparticles Of Non-LinearHydrophilic-Hydrophobic Multiblock Copolymers; U.S. Pat. No. 5,562,099Polymeric Microparticles Containing Agents For Imaging; U.S. Pat. No.5,545,409 Delivery System For Controlled Release Of Bioactive Factors;U.S. Pat. No. 5,543,158 Biodegradable Injectable Nanoparticles; U.S.Pat. No. 5,514,378 Biocompatible Polymer Membranes And Methods OfPreparation Of Three Dimensional Membrane Structures; U.S. Pat. No.5,512,600 Preparation Of Bonded Fiber Structures For Cell Implantation;U.S. Pat. No. 5,500,161 Method For Making Hydrophobic PolymericMicroparticles; U.S. Pat. No. 5,487,390 Gas-filled polymericmicrobubbles for ultrasound imaging; U.S. Pat. No. 5,399,665Biodegradable polymers for cell transplantation; U.S. Pat. No. 5,356,630Delivery system for controlled release of bioactive factors; U.S. Pat.No. 5,330,768 Controlled drug delivery using polymer/pluronic blends;U.S. Pat. No. 5,286,763 Bioerodible polymers for drug delivery in bone;U.S. Pat. No. 5,149,543 Tonically cross-linked polymeric microcapsules;U.S. Pat. No. 5,128,420 Method of making hydroxamic acid polymers fromprimary amide polymers; U.S. Pat. No. 5,122,367 Polyanhydridebioerodible controlled release implants for administration of stabilizedgrowth hormone; U.S. Pat. No. 5,100,668 Controlled release systemscontaining heparin and growth factors; U.S. Pat. No. 5,019,379Unsaturated polyanhydrides; U.S. Pat. No. 5,010,167 Poly(amide-andimide-co-anhydride) for biological application; U.S. Pat. No. 4,948,587Ultrasound enhancement of transbuccal drug delivery; U.S. Pat. No.4,946,929 Bioerodible articles useful as implants and prostheses havingpredictable degradation rates; U.S. Pat. No. 4,933,431 One steppreparation of poly(amide-anhydride); U.S. Pat. No. 4,933,185 System forcontrolled release of biologically active compounds; U.S. Pat. No.4,921,757 System for delayed and pulsed release of biologically activesubstances; U.S. Pat. No. 4,916,204 Pure polyanhydride from dicarboxylicacid and coupling agent; U.S. Pat. No. 4,906,474 Bioerodiblepolyanhydrides for controlled drug delivery; U.S. Pat. No. 4,900,556System for delayed and pulsed release of biologically active substances;U.S. Pat. No. 4,898,734 Polymer composite for controlled release ormembrane formation; U.S. Pat. No. 4,891,225 Bioerodible polyanhydridesfor controlled drug delivery; U.S. Pat. No. 4,888,176 Controlled drugdelivery high molecular weight polyanhydrides; U.S. Pat. No. 4,886,870Bioerodible articles useful as implants and prostheses havingpredictable degradation rates; U.S. Pat. No. 4,863,735 Biodegradablepolymeric drug delivery system with adjuvant activity; U.S. Pat. No.4,863,611 Extracorporeal reactors containing immobilized species; U.S.Pat. No. 4,861,627 Preparation of multiwall polymeric microcapsules;U.S. Pat. No. 4,857,311 Polyanhydrides with improved hydrolyticdegradation properties; U.S. Pat. No. 4,846,786 Bioreactor containingsuspended, immobilized species; U.S. Pat. No. 4,806,621 Biocompatible,bioerodible, hydrophobic, implantable polyimino carbonate article; U.S.Pat. No. 4,789,724 Preparation of anhydride copolymers; U.S. Pat. No.4,780,212 Ultrasound enhancement of membrane permeability; U.S. Pat. No.4,779,806 Ultrasonically modulated polymeric devices for deliveringcompositions; U.S. Pat. No. 4,767,402 Ultrasound enhancement oftransdermal drug delivery; U.S. Pat. No. 4,757,128 High molecular weightpolyanhydride and preparation thereof; U.S. Pat. No. 4,657,543Ultrasonically modulated polymeric devices for delivering compositions;U.S. Pat. No. 4,638,045 Non-peptide polyamino acid bioerodible polymers;U.S. Pat. No. 4,591,496 Process for making systems for the controlledrelease of macromolecules.

Drug Delivery on a Stent, Balloon or Other Device

The compounds and compositions of the present invention can be deliveredvia a medical device. Any insertable or implantable medical device,including, but not limited to stents, catheters, balloon catheters,shunts or coils. In one embodiment, the present invention providesmedical devices, such as stents, the surface of which is coated with acompound or composition as described herein. The medical device of thisinvention can be used, for example, in any application for treating,preventing, or otherwise affecting the course of a disease or tissue ororgan dysfunction, such as the diseases disclosed herein. A stent canbeany tubular structure used to maintain or support a bodily orifice orcavity. Stent can be a scaffolding, usually cylindrical in shape, thatcan be inserted into a body passageway or a portion of a bodypassageway, which has been narrowed, irregularly contured, obstructed,or occluded by a disease process in order to prevent closure orreclosure of the passageway. Stents act by physically holding open thewalls of the body passage into which they are inserted. A ballooncatheter can be a tubular instrument with a balloon or multiple balloonsthat can be inflated or deflated without removal after insertion intothe body.

Additional examples of implantable medical devices include, but are notlimited to, stents, stent grafts, stent covers, catheters, artificialheart valves and heart valve scaffolds, venous access devices, vena cavafilters, peritoneal access devices, and enteral feeding devices used inpercutaneous endoscopic gastronomy, prosthetic joints and artificialligaments and tendons. Stents include, but are not limited to esophagealstents, vascular stents, biliary stents, pancreatic stents, ureteric andurethral stents, lacrimal stents, Eustachian tube stents, fallopian tubestents and tracheal/bronchial stents. Stents can be coiled or patternedas a braided or woven open network of fibers or filaments or, forexample, as an interconnecting open network of articulable segments.Such stent designs can be useful for maintaining the patency of a bodylumen such as a coronary artery. Stents adapted primarily to providedrainage, in contrast to stents adapted primarily to support a bodylumen, can have a continuous wall structure in contrast to an opennetwork wall structure.

Stents can be readily obtained from commercial sources, or constructedin accordance with well-known techniques. Representative examples ofstents include those described in U.S. Pat. No. 4,768,523, entitled“Hydrogel Adhesive;” U.S. Pat. No. 4,776,337, entitled “ExpandableIntraluminal Graft, and Method and Apparatus for Implanting andExpandable Intraluminal Graft;” U.S. Pat. No. 5,041,126 entitled“Endovascular Stent and Delivery System;” U.S. Pat. No. 5,052,998entitled “Indwelling Stent and Method of Use;” U.S. Pat. No. 5,064,435entitled “Self-Expanding Prosthesis Having Stable Axial Length;” U.S.Pat. No. 5,089,606, entitled “Water-insoluble Polysaccharide HydrogelFoam for Medical Applications;” U.S. Pat. No. 5,147,370, entitled“Nitinol Stent for Hollow Body Conduits;” U.S. Pat. No. 5,176,626,entitled “Indwelling Stent;” U.S. Pat. No. 5,213,580, entitled“Biodegradable polymeric Endoluminal Sealing Process;” and U.S. Pat. No.5,328,471, entitled “Method and Apparatus for Treatment of Focal Diseasein Hollow Tubular Organs and Other Tissue Lumens.”

Stents can be coated with the compounds and compositions of the presentinvention in a variety of manners known to one skilled in the art,including, but not limited to: (a) by directly affixing to the stent ancompound or composition described herein (e.g., by either spraying thestent with a polymer/drug film, or by dipping the stent into apolymer/drug solution), (b) by coating the stent with a substance suchas a hydrogel which will in turn absorb the compounds or compositions,(c) by interweaving compounds or composition coated thread (or thepolymer itself formed into a thread) into the stent structure, (d) byinserting the stent into a sleeve or mesh which is comprised of orcoated with a compounds or composition of the present invention, or (e)constructing the stent itself with a compounds or composition describedherein. Therefore, in one embodiment of the present invention, thecompounds are applied, attached, dripped and/or embedded to the stent byknown methods. Within particular embodiments of the invention, thecomposition should firmly adhere to the stent during storage and at thetime of insertion, and should not be dislodged from the stent when thediameter is expanded from its collapsed size to its full expansion size.The composition should also preferably not degrade during storage, priorto insertion, or when warmed to body temperature after expansion insidethe body. In addition, it can coat the stent smoothly and evenly, with auniform distribution of the compound, while not changing the stentcontour.

In one embodiment, the stent structure can include a plurality of holesor, in a separate embodiment, a plurality of recesses which can act asreservoirs and can be loaded with the drug. The stent can be designedwith particular sites that can incorporate the drug, or multiple drugs,optionally with a biodegradable or non-biodegradable matrix. The sitescan be holes, such as laser drilled holes, or recesses in the stentstructure that can be filled with the drug or can be partially filledwith the drug. In one embodiment, a portion of the holes are filled withother therapeutic agents, or with materials that regulate the release ofthe drug or drugs. One advantage of this system is that the propertiesof the coating can be optimized for biocompatibility and adhesionproperties, without the addition requirement of being able to load andrelease the drug. The size, shape, position, and number of reservoirscan be used to control the amount of drug, and therefore the dosedelivered.

Within another aspect of the present invention, methods are provided forexpanding the lumen of a body passageway, comprising inserting a stentinto the passageway, the stent having a generally tubular structure, thesurface of the structure being coated with a compound or composition ofthe present invention, such that the passageway is expanded.

Generally, stents can be inserted in a similar fashion regardless of thesite or the disease being treated, such as via techniques known to oneskilled in the art. Briefly, a preinsertion examination, usually adiagnostic imaging procedure, endoscopy, or direct visualization at thetime of surgery, is generally first performed in order to determine theappropriate positioning for stent insertion. A guidewire is thenadvanced through the lesion or proposed site of insertion, and over thisis passed a delivery catheter which allows a stent in its collapsed formto be inserted. Typically, stents are capable of being compressed, sothat they can be inserted through tiny cavities via small catheters, andthen expanded to a larger diameter once they are at the desiredlocation. Once expanded, the stent physically forces the walls of thepassageway apart and holds them open. As such, they are capable ofinsertion via a small opening, and yet are still able to hold open alarge diameter cavity or passageway. The stent can be self-expanding(e.g., the Wallstent and Gianturco stents), balloon expandable (e.g.,the Palmaz stent and Strecker stent), or implanted by a change intemperature (e.g., the Nitinol stent).

Stents can be maneuvered into place under radiologic or direct visualcontrol, taking particular care to place the stent precisely across thenarrowing in the organ being treated. The delivery catheter is thenremoved, leaving the stent standing on its own as a scaffold. A postinsertion examination, usually an x-ray, is often utilized to confirmappropriate positioning.

VI. Therapeutic Uses

The formulations comprising the compound of the present invention can beused for a number of therapeutic applications. Notably, the compoundscan be used to treat disorders characterized by abnormal cellproliferation, inflammation, or both abnormal proliferation andinflammation.

A. Disorders of Abnormal Cell Proliferation

The compositions of the present invention are useful in the treatment orprevention of abnormal cell proliferation. As used herein, a “abnormalcell proliferation disorder” refers to a disease or disordercharacterized by the inappropriate growth or multiplication of one ormore cell types relative to the growth of that cell type or types in anindividual not suffering from that disease or disorder. Abnormal cellproliferation has been shown to be the root of many diseases anddisorders, including cancer and non-cancer disorders which present aserious health threat.

The term “treatment” refers to methods of killing, inhibiting or slowingthe growth or increase in size of a body or population of abnormallyproliferative cells or tumor or cancerous growth, reducing the number ofcells in the population of abnormally proliferative cells, or preventingthe spread of abnormally proliferative cells to other anatomic sites, aswell as reducing the size of a growth of abnormally proliferative cells.The term “treatment” does not necessarily mean to imply a cure or acomplete abolition of the disorder of abnormal cell proliferation. Theterm “prevention” refers to methods to which slow, delay, control ordecrease the likelihood of the incidence or onset of disorders ofabnormal cell proliferation, in comparison to that which would occur inthe absence of treatment.

Abnormal cellular proliferation, notably hyperproliferation, can occuras a result of a wide variety of factors, including genetic mutation,infection, exposure to toxins, autoimmune disorders, and benign ormalignant tumor induction. Hyperproliferative cell disorders include,but are not limited to, skin disorders, blood vessel disorders,cardiovascular disorders, fibrotic disorders, mesangial disorders,autoimmune disorders, graft-versus-host rejection, tumors and cancers.

Non-Neoplastic Abnormal Cellular Proliferation Disorders

Skin disorders associated with cellular hyperproliferation, including,but are not limited to, psoriasis (all types), eczema, acne vulgaris,acne, rosacea, common warts, anogenital (venereal) warts, eczema; lupusassociated skin lesions; dermatitides such as atopic dermatitis,seborrheic dermatitis and solar dermatitis; keratoses such as seborrheickeratosis, senile keratosis, actinic keratosis, photo-induced keratosis,skin ageing, including photo-induced skin aging, keratosis follicularis;keloids, eukoplakia, lichen planus, keratitis, contact dermatitis,urticaria, pruritus, hidradenitis, and acne inverse; pemphigus vulgaris,actinic keratosis, basal cell carcinoma and squamous cell carcinoma.

In a particular embodiment, the compounds of the present invention areuseful in the treatment of psoriasis. Psoriasis is an immune-mediatedskin disorder characterized by chronic T-cell stimulation byantigen-presenting cells (APC) occurs in the skin. Approximately 2-3% ofthe global population is afflicted by psoriasis. While the cause ofpsoriasis remains poorly understood, it appears to result from acombination of genetic and environmental factors. The various types ofpsoriasis include, for example, plaque psoriasis (i.e., vulgarispsoriasis), pustular psoriasis, guttate psoriasis, inverse psoriasis,erythrodermic psoriasis, psoriatic arthritis, scalp psoriasis and nailpsoriasis. Psoriasis is a lifelong disease characterized by spontaneousremissions and exacerbations. Common systemic treatments for psoriasisinclude methotrexate, cyclosporin and oral retinoids, but their use islimited by toxicity. Up to 40% of patients with psoriasis also developpsoriatic arthritis (Kormeili T et al. Br J Dermatol. (2004)151(1):3-15.

Blood vessel proliferative disorders include vasculogenic (formation)and angiogenic (spreading) disorders which result in abnormalproliferation of blood vessels. Other blood vessel proliferativedisorders include arthritis and ocular diseases such as diabeticretinopathy. Abnormal neovascularization is also associated with solidtumors. In a particular embodiment, the compounds of the presentinvention are useful in the treatment of diseases associated withuncontrolled angiogenesis Representative, non-limiting diseases ofabnormal angiogenesis include, e.g, rheumatoid arthritis,ischemic-reperfusion related brain edema and injury, cortical ischemia,ovarian hyperplasia and hypervascularity, (polycystic ovary syndrome),endometriosis, psoriasis, diabetic retinopathy, and other ocularangiogenic diseases such as retinopathy of prematurity (retrolentalfibroplastic), macular degeneration, corneal graft rejection,neuroscular glaucoma and Oster Webber syndrome. Cancers associated withabnormal blood cell proliferation include hemangioendotheliomas,hemangiomas and Kaposi's sarcoma.

Disorders of the cardiovascular system involving abnormal cellproliferation include, for example, hypertension, vasculo-occlusivediseases (e.g., atherosclerosis, thrombosis and restenosis afterangioplasty), acute coronary syndromes such as unstable angina,myocardial infarction, ischemic and non-ischemic cardiomyopathies,post-MI cardiomyopathy and myocardial fibrosis, substance-inducedcardiomyopathy.

Atherosclerosis represents one type of abnormal smooth muscle cellproliferation. As used herein, atheroscloeris refers to classicalatherosclerosis, accelerated atherosclerosis, atherosclerotic lesionsand any other arteriosclerotic conditions characterized by undesirableendothelial and/or vascular smooth muscle cell proliferation, includingvascular complications of diabetes. Classical atheroscloeris ischaracterized by proliferation of vascular smooth muscle cells. Growthfactors released from endothelial cells are thought to stimulate theproliferation of subintimal smooth muscle which, in turn, reduces thecaliber and finally obstructs the artery. The invention is useful ininhibiting such proliferation, and therefore in delaying the onset of,inhibiting the progression of, or even stopping the progression of suchproliferation. Accelerated atherosclerosis is responsible for thefailure of many heart transplants that are not rejected. Here,proliferation is also mediated by growth factors, and can produceobstruction of the coronary arteries.

Vascular injury can also result in endothelial and vascular smoothmuscle cell proliferation. The injury can be caused by traumatic eventsor interventions (e.g., angioplasty, vascular graft, anastomosis, organtransplant) (Clowes A et al. A. J. Vasc. Surg (1991) 13:885). Restenosis(e.g. coronary, carotid, and cerebral lesions) is the main complicationof successful balloon angioplasty of the coronary arteries. It isbelieved to be caused by the release of growth factors as a result ofmechanical injury to the endothelial cells lining the coronary arteries.

Other atherosclerotic conditions which can be treated or prevented bymeans of the present invention include diseases of the arterial wallsthat involve proliferation of endothelial and/or vascular smooth musclecells, including complications of diabetes, diabetic glomerulosclerosisand diabetic retinopathy.

Abnormal cell proliferation disorders associated the endocrine systeminclude, for example, insulin resistant states including obesity,diabetes mellitus (types 1 & 2), diabetic retinopathy, maculardegeneration associated with diabetes, gestational diabetes, impairedglucose tolerance, polycystic ovarian syndrome; osteoporosis,osteopenia, accelerated aging of tissues and organs including Werner'ssyndrome.

The compositions and methods of the present invention are also usefulfor treating inflammatory diseases associated with abnormal cellproliferation. These include, but are not limited, to inflammatory boweldisease (IBD), rheumatoid arthritis (RA), multiple sclerosis (MS),proliferative glomerulonephritis, lupus erythematosus, scleroderma,temporal arteritis, thromboangiitis obliterans, mucocutaneous lymph nodesyndrome, asthma, host versus graft, thyroiditis, Grave's disease,antigen-induced airway hyperactivity, pulmonary eosinophilia,Guillain-Barre syndrome, allergic rhinitis, myasthenia gravis, humanT-lymphotrophic virus type 1-associated myelopathy, herpes simplexencephalitis, inflammatory myopathies; atherosclerosis, andGoodpasture's syndrome. These diseases are considered in more detailbelow, under “Disorders of Inflammation.”

Abnormal cell proliferation disorders of the urogenital system can alsobe treated according to the present invention. These include, forexample, edometriosis, benign prostatic hyperplasia, eiomyoma,polycystic kidney disease, and diabetic nephropathy.

Treatment of fibrotic disorders is contemplated in the presentinvention. As used herein, fibrotic disorders refers to fibrosis andother medical complications of fibrosis which result in whole or in partfrom the proliferation of fibroblasts. Medical conditions involvingfibrosis include undesirable tissue adhesion resulting from surgery orinjury. Non-limiting examples of fibrotic disorders include hepaticcirrhosis and mesangial proliferative cell disorders.

Abnormal cell proliferation disorders of the tissues and joints can betreated according to the present invention including, for example,Raynaud's phenomenon/disease, Sjogren's Syndrome systemic sclerosis,systemic lupus erythematosus, vasculitides, ankylosing spondylitis,osteoarthritis, reactive arthritis, psoriatic arthritis, fibromyalgia.

Mesangial disorders are brought about by abnormal proliferation ofmesangial cells. Mesangial hyperproliferative cell disorders includevarious human renal diseases, such as glomerulonephritis, diabeticnephropathy, malignant nephrosclerosis, thrombotic microangiopathysyndromes, transplant rejection, and glomerulopathies.

Abnormal cell proliferation disorders of the pulmonary system can alsobe treated according to the present invention including, for example,asthma, chronic obstructive pulmonary disease (COPD), reactive airwaydisease, pulmonary fibrosis, pulmonary hypertension.

Other disorders that can include an abnormal cellular proliferativecomponent include Behcet's syndrome, Fibrocystic breast disease,fibroadenoma, chronic fatigue syndrome, acute respiratory distresssyndrome (ARDS), ischemic heart disease, post-dialysis syndrome,leukemia, acquired immune deficiency syndrome, vasculitis, lipidhistiocytosis, septic shock, familial intestinal polyposes such asGardner syndrome.

Also included in the scope of disorders that may be treated by thecompositions and methods of the present invention are virus-inducedhyperproliferative diseases including, for example, human papillomavirus-induced disease (e.g., lesions caused by human papilloma virusinfection), Epstein-Barr virus-induced disease, scar formation, genitalwarts, cutaneous warts, and the like.

Neoplastic Abnormal Cellular Proliferation Disorders

Diseases of abnormal cell proliferation include various types of cancerssuch as primary tumors and tumor metastasis. The term “cancer” includesboth tumor-forming or non-tumor forming cancers. As used herein, theterm “tumor” means an abnormal mass of cells within a multicellularorganism. Generally, the growth of the abnormal cells of the tumorexceeds and is uncoordinated with that of normal cells. Furthermore, theabnormal growth of tumor cells generally persists in an abnormal (i.e.,excessive) manner after the cessation of stimuli that originally causedthe abnormality in the growth of the cells. Tumors can be malignant orbenign. A benign tumor is characterized by cells that retain theirdifferentiated features and do not divide in a completely uncontrolledmanner. A benign tumor is usually localized and nonmetastatic. Specifictypes benign tumors that can be treated using the present inventioninclude hemangiomas, hepatocellular adenoma, cavernous haemangioma,focal nodular hyperplasia, acoustic neuromas, neurofibroma, bile ductadenoma, bile duct cystanoma, fibroma, lipomas, leiomyomas,mesotheliomas, teratomas, myxomas, nodular regenerative hyperplasia,trachomas and pyogenic granulomas.

A malignant tumor (i.e., cancer) is characterized by cells that areundifferentiated, do not respond to the body's growth control signals,and multiply in an uncontrolled manner one. Maligant tumors are invasiveand capable of metastasis. Representative, non-limiting cancers includebreast cancer, skin cancer, bone cancer, prostate cancer, liver cancer,lung cancer, brain cancer, cancer of the larynx, gallbladder, pancreas,rectum, parathyroid, thyroid, adrenal, neural tissue, head and neck,colon, stomach, bronchi, kidneys, basal cell carcinoma, squamous cellcarcinoma of both ulcerating and papillary type, metastatic skincarcinoma, osteo sarcoma, Ewing's sarcoma, veticulum cell sarcoma,myeloma, giant cell tumor, small-cell lung tumor, gallstones, islet celltumor, primary brain tumor, acute and chronic lymphocytic andgranulocytic tumors, hairy-cell tumor, adenoma, hyperplasia, medullarycarcinoma, pheochromocytoma, mucosal neurons, intestinalganglloneuromas, hyperplastic corneal nerve tumor, marfanoid habitustumor, Wilm's tumor, seminoma, ovarian tumor, leiomyomater tumor,cervical dysplasia and in situ carcinoma, neuroblastoma, retinoblastoma,soft tissue sarcoma, malignant carcinoid, topical skin lesion, mycosisfungoide, rhabdomyosarcoma, Kaposi's sarcoma, osteogenic and othersarcoma, malignant hypercalcemia, renal cell tumor, polycythermia vera,adenocarcinoma, glioblastoma multiforma, leukemias, lymphomas, malignantmelanomas, epidermoid carcinomas, and other carcinomas and sarcomas.

The compounds of the present invention are also useful in preventing ortreating proliferative responses associated with organ transplantationwhich contribute to rejections or other complications. For example,proliferative responses may occur during transplantation of the heart,lung, liver, kidney, and other body organs or organ systems.

B. Inflammation Disorders

The compounds of the present invention are also useful in the treatmentof diseases characterized by inflammation. Diseases and disorders whichhave significant inflammatory components are ubiquitous and include, forexample, skin disorders, bowel disorders, certain degenerativeneurological disorders, arthritis, autoimmune diseases and a variety ofother illnesses. Some of these diseases have both an inflammatory andproliferative component, as described above under “Abnormal CellProliferation.”

(i) Inflammatory Bowel Disease

Inflammatory bowel diseases (IBD) includes several chronic inflammatoryconditions, including Crohn's disease (CD) and ulcerative colitis (UC).Collectively, these diseases afflict between one and two millionAmericans and produce symptoms that impair quality of life and abilityto function. Both CD and UC are considered “idiopathic” because theiretiology is unknown. While the Crohn's disease and ulcerative colitisshare many symptoms (e.g., diarrhea, abdominal pain, fever, fatigue),ulcerative colitis is limited to the colon whereas Crohn's disease caninvolve any segment of the gastrointestinal tract. Both diseases mayinvolve extraintestinal manifestations, including arthritis, diseases ofthe eye (e.g., episcleritis and iritis), skin diseases (e.g., erythemanodosum and pyoderma gangrenosum), urinary complications, gallstones andanemia. Strokes, retinal thrombi, and pulmonary emboli are not uncommon,because many patients are in a hypercoagulable state.

While the etiology of IBD is unclear, a combination of environmental,infectious, genetic, autoimmune, and host factors have been suspected.Interactions among these factors may be more important. From a geneticstandpoint, IBD is thought to involve genetically determined,deregulated immune responses to otherwise innocuous luminal antigens(Rev Lim W C. Gastroenterol Disord. (2004) 4(2):66-85). Bacterialorganisms that can produce IBD include, for example, Shigella,Salmonella, Campylobacter, H. pylori, and some E. coli. Bacteria are acommon cause of acute self-limited colitis—active IBD without chronicchanges. Recently, a clear association between complicated courses ofulcerative colitis and the presence of cytomegalovirus (CMV) has beenestablished (Hommes D W. Inflamm Bowel Dis. (2004) 10(3):245-50).

In a particular embodiment, the compounds of the present invention,including pharmaceutically acceptable salts, prodrugs and estersthereof, are useful in the treatment of inflammatory bowel disease. In apreferred embodiment, the inflammatory bowel disease is Crohn's disease.

(ii) Chronic Obstructive Pulmonary Disease

Chronic Obstructive Pulmonary Disease, or COPD, is characterized by anot fully reversible airflow limitation which is progressive andassociated with an abnormal inflammatory reaction of the lungs. It isone of the commonest respiratory conditions of adults, a major cause ofchronic morbidity and mortality, and represents a substantial economicand social burden worldwide (Pauwels R A. Lancet. (2004)364(9434):613-20). In the United States, COPD is currently the fourthleading cause of death (Molfino N A. Chest. (2004) 125(5):1929-40). Themajor risk factors for the development of COPD are inhaled toxicsubstances, such as smoke. Other names for the disorder include, forexample, Chronic Obstructive Airways Disease, (COAD); ChronicObstructive Lung Disease, (COLD), Chronic Airflow Limitation, (CAL orCAFL) and Chronic Airflow Obstruction (COA).

Chronic obstructive pulmonary disease (COPD) COPD is characterized bychronic inflammation throughout the airways, parenchyma, and pulmonaryvasculature. The inflammation involves a multitude of cells, mediators,and inflammatory effects. Mediators include, for example, mediatorsinclude proteases, oxidants and toxic peptides. Over time, inflammationdamages the lungs and leads to the pathologic changes characteristic ofCOPD. Manifestations of disease includes both chronic bronchitis andemphysema. Chronic bronchitis is a long-standing inflammation of theairways that produces a lot of mucus, causing wheezing and infections.It is considered chronic if a subject has coughing and mucus on aregular basis for at least three months a year and for two years in arow. Emphysema is a disease that destroys the alveolae and/or bronchae,causing the air sacs to become enlarged, thus making breathingdifficult. Most common in COPD patients is the centrilobular form ofemphysema.

In a particular embodiment, the compounds of the present invention areuseful in the treatment of chronic obstructure pulmonary disease.

Sarcoidois

Sarcoidois is yet another chronic inflammatory disease with associatedabnormal cell proliferation. Sarcoidois is a multisystem granulomatousdisorder. The granulomas are created by the angiogenic capillary sproutsproviding a constant supply of inflammatory cells. Psoriasis, also achronic and recurrent inflammatory disease, is characterized by papulesand plaques of various sizes. Treatment with the compounds of thepresent invention would prevent the formation of new blood vesselsnecessary to maintain the characteristic lesions.

(iv) Asthma

In recent years, it has become clear that the primary underlyingpathology of asthma is airway tissue inflammation (Lemanke R F.Pediatrics. (2002)109(2):368-372; Nagayama Y et al. Pediatr AllergyImmunol. (1995) 6:204-208). Asthma is associated with a wide range ofsymptoms and signs, including wheezing, cough, chest tightness,shortness of breath and sputum production. Airway inflammation a keyfeature of asthma pathogenesis and its clinical manifestations.Inflammatory cells, including mast cells, eosinophils, and lymphocytes,are present even in the airways of young patients with mild asthma.Inflammation also plays a role in wheezing disorders, with or withoutasthma.

(v) Arthritis and Osteoarthritis

Arthritis means joint inflammation. More than 40 million Americanssuffer from arthritis in its various forms, including includes over 100kinds of rheumatic diseases (i.e., diseases affecting joints, muscle,and connective tissue, which makes up or supports various structures ofthe body, including tendons, cartilage, blood vessels, and internalorgans). Representative types of arthritis include rheumatoid (such assoft-tissue rheumatism and non-articular rheumatism), fibromyalgia,fibrositis, muscular rheumatism, myofascil pain, humeral epicondylitis,frozen shoulder, Tietze's syndrome, fascitis, tendinitis, tenosynovitis,bursitis), juvenile chronic, spondyloarthropaties (ankylosingspondylitis), osteoarthritis, hyperuricemia and arthritis associatedwith acute gout, chronic gout and systemic lupus erythematosus.

Hypertrophic arthritis or osteoarthritis is the most common form ofarthritis. It is characterized by the breakdown of the joint'scartilage. Osteoarthritis is common in people over 65, but may appeardecades earlier. Breakdown of the cartilage causes bones to rub againsteach other, causing pain and loss of movement. In recent years, therehas been increasing evidence that inflammation plays an important rolein osteoarthritis. Nearly one-third of patients ready to undergo jointreplacement surgery for osteoarthritis (OA) had severe inflammation inthe synovial fluid that surrounds and protects the joints.

In a particular embodiment, the compounds of the present invention areuseful in the treatment of osteoarthritis.

The second most common form of arthritis is rheumatoid arthritis. It isan autoimmune disease that can affect the whole body, causing weakness,fatigue, loss of appetite, and muscle pain. Typically, the age of onsetis much earlier than osteoarthritis, between ages 20 and 50.Inflammation begins in the synovial lining and can spread to the entirejoint.

Other forms of arthritis include, for example, gout, ankylosingspondylitis, juvenile arthritis, psoriatic arthritis, systemic lupuserythematosus, infectious arthritis, scleroderma, and fibromyalgiasyndrome. Asthma is sometimes classified by the triggers that may causean asthma episode (or asthma attack) or the things that make asthmaworse in certain individuals, such as occupational asthma, exerciseinduced asthma, nocturnal asthma, or steroid resistant asthma.

(vii) Cardiovascular Disease

As noted above, inflammation also plays an important role in thepathogenesis of cardiovascular diseases, including restenosis,atherosclerotic complications resulting from plaque rupture, severetissue ischemia, and heart failure. Inflammatory changes in the arterialwall, for example, are thought to play a major role in the developmentof restenosis and atherosclerosis (Ross R. N Engl J Med. (1999) 340:115-126). Local inflammation occurs in the formation the plaques alsocontributes to the weakening of the fibrous cap of the advanced plaque,ultimately resulting in plaque rupture and acute coronary syndromes(Lind L. Atherosclerosis. (2003) 169(2):203-14. Evidence suggests thatmediators such as adhesion molecules, chemokines and cytokines areinvolved in the initiation and progression of atherosclerotic lesions.Dynamic instability of a coronary atherosclerotic plaque is understoodas the foundation for the development of unstable angina and myocardialinfarction (Smith D. Circulation. (2001) 104(7):746-9.

(ix) Multiple Sclerosis

Multiple sclerosis (MS) is a chronic, often debilitating autoimmunedisease that affects the central nervous system. MS is characterized byinflammation which results when the The body directs antibodies andwhite blood cells against proteins in the myelin sheath, fatty materialwhich insulates the nerves in the brain and spinal cord. The result maybe multiple areas of scarring (sclerosis), which slows or blocks musclecoordination, visual sensation and other nerve signals. The severity ofthe disease may vary. Most MS patients have a relapsing form of thedisease, involving exacerbations in which symptoms appear suddenly(i.e., within 24 hours). Various “triggers” of exacerbation have beenproposed, including bacterial or viral infections that cause T cells tomistake myelin proteins for these antigens, bacterial superantigens,physical injury, or stressful life events (Hohlfeld R. Neurology (1995)45(6 suppl 6): S33-8).

In a particular embodiment, the compounds of the present invention areuseful in the treatment of multiple sclerosis.

(x) Neurological Disease

Inflammatory have been shown to be associated with the pathogenesis ofneurological disorders, including Parkinson's disease and Alzheimer'sdisease (Mirza B. et al. Neuroscience (2000) 95(2):425-32; Gupta A. IntJ Clin Pract. (2003) 57(1):36-9; Ghatan E. et al. Neurosci Biobehav Rev.(1999) 23(5):615-33).

(ix) Other Inflammatory Diseases

The present invention is also useful in the treatment of, for example,allergic disorders, allergic rhinitis, skin disorders, transplantrejection, poststreptococcal and autoimmune renal failure, septic shock,systemic inflammatory response syndrome (SIRS), adult respiratorydistress syndrome (ARDS), envenomation, lupus erythmatosus, myastheniagravis, Grave's disease, Hashimoto's thyroiditis, autoimmune hemolyticanemias, insulin dependent diabetes mellitus, glomerulonephritis, andrheumatic fever, pelvic inflammatory disease (PID), conjunctivitis,dermatitis, bronchitis, and rhinitis.

VII. Combination Therapies

Any of the compounds disclosed herein can be administered in combinationor alternation with a second, and perhaps third, biologically activeagent to increase its effectiveness against the target disorder. Incombination therapy, effective dosages of two or more agents areadministered together. In alternation therapy, an effective dosage ofeach agent is administered serially.

In general, combination therapy is typically preferred over alternationtherapy because it induces multiple simultaneous stresses on thecondition. Any method of alternation can be used that provides treatmentto the patient. Nonlimiting examples of alternation patterns include 1-6weeks of administration of an effective amount of one agent followed by1-6 weeks of administration of an effective amount of a second agent.The alternation schedule can include periods of no treatment.Combination therapy generally includes the simultaneous administrationof an effective ratio of dosages of two or more active agents.

Illustrative examples of specific agents that can be used in combinationor alternation with the compounds of the present invention are describedbelow. These agents can alternatively be in combination with thecompounds of the present invention to treat a host suffering from any ofthe other disorders listed in Section F above.

A. Abnormal Cell Proliferation

The compounds of the present invention can be used in combination oralternation with antiproliferative agents. As used herein, anantiproliferative agent is a compound that decreases thehyperproliferation of cells. Proliferative disorders are currentlytreated by a variety of classes of compounds including alkylatingagents, antimetabolites, natural products, enzymes, biological responsemodifiers, miscellaneous agents, radiopharmaceuticals (for example, Y-90tagged to hormones or antibodies), hormones and antagonists. Any of theantiproliferative agents listed below or any other such therapeuticagents and principles as described in, for example, DeVita, V. T., Jr.,Hellmann, S., Rosenberg, S. A.; In: Cancer: Principles & Practice ofOncology, 5th ed., Lippincott-Raven Publishers (1997) can be used incombination with the compounds of the present invention.

Anti-Angiogenesis Agents

Representative, nonlimiting examples of anti-angiogenesis agentssuitable for use in combination with the compounds of the presentinvention include, but are not limited to, retinoid acid and derivativesthereof, 2-methoxyestradiol, Angiostatin™ protein, Endostatin™ protein,suramin, squalamine, tissue inhibitor of metalloproteinase-I, tissueinhibitor of metalloproteinase-2, plasminogen activator inhibitor-1,plasminogen activator inhibitor-2, cartilage-derived inhibitor,paclitaxel, platelet factor 4, protamine sulphate (clupeine), sulphatedchitin derivatives (prepared from queen crab shells), sulphatedpolysaccharide peptidoglycan complex (sp-pg), staurosporine, modulatorsof matrix metabolism, including for example, proline analogs((I-azetidine-2-carboxylic acid (LACA), cishydroxyproline,d,1-3,4-dehydroproline, thiaproline], α,α-dipyridyl,β-aminopropionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone;methotrexate, mitoxantrone, heparin, interferons, 2 macroglobulin-serum,chimp-3, chymostatin, β-cyclodextrin tetradecasulfate, eponemycin;fumagillin, gold sodium thiomalate, d-penicillamine (CDPT),β-1-anticollagenase-serum, α-2-antiplasmin, bisantrene, lobenzaritdisodium, n-(2-carboxyphenyl-4-chloroanthronilic acid disodium or “CCA”,thalidomide; angiostatic steroid, cargboxynaminolmidazole;metalloproteinase inhibitors such as BB94. Other anti-angiogenesisagents include antibodies, preferably monoclonal antibodies againstthese angiogenic growth factors: bFGF, aFGF, FGF-5, VEGF isoforms,VEGF-C, HGF/SF and Ang-1/Ang-2. Ferrara N. and Alitalo, K. “Clinicalapplication of angiogenic growth factors and their inhibitors” (1999)Nature Medicine 5:1359-1364.

(ii) Alkylating Agents

Representative, nonlimiting examples of alkylating agents suitable foruse in combination with the compounds of the present invention include,but are not limited to, Nitrogen Mustards, such as Mechlorethamine(Hodgkin's disease, non-Hodgkin's lymphomas), Cyclophosphamide,Ifosfamide (acute and chronic lymphocytic leukemias, Hodgkin's disease,non-Hodgkin's lymphomas, multiple myeloma, neuroblastoma, breast, ovary,lung, Wilms' tumor, cervix, testis, soft-tissue sarcomas), Melphalan(L-sarcolysin) (multiple myeloma, breast, ovary), Chlorambucil (chroniclymphoctic leukemia, primary macroglobulinemia, Hodgkin's disease,non-Hodgkin's lymphomas); Ethylenimines and Methylmelamines, such as,Hexamethylmelamine (ovary), Thiotepa (bladder, breast, ovary); AlkylSulfonates, such as, Busulfan (chronic granuloytic leukemia);Nitrosoureas, such as, Carmustine (BCNU) (Hodgkin's disease,non-Hodgkin's lymphomas, primary brain tumors, multiple myeloma,malignant melanoma), Lomustine (CCNU) (Hodgkin's disease, non-Hodgkin'slymphomas, primary brain tumors, small-cell lung), Semustine(methyl-CCNU) (primary brain tumors, stomach, colon), Streptozocin (STR)(malignant pancreatic insulinoma, malignant carcinoin); Triazenes, suchas, Dacarbazine (DTIC; dimethyltriazenoimidazole-carboxamide) (malignantmelanoma, Hodgkin's disease, soft-tissue sarcomas).

(iii) Antimetabolites

Representative, nonlimiting examples of anti-metabolite agents suitablefor use in combination with the compounds of the present inventioninclude, but are not limited to, Folic Acid Analogs, such as,Methotrexate (amethopterin) (acute lymphocytic leukemia,choriocarcinoma, mycosis fungoides, breast, head and neck, lung,osteogenic sarcoma); Pyrimidine Analogs: Fluorouracil (5-fluorouracil;5-FU) Floxuridine (fluorodeoxyuridine; FUdR) (breast, colon, stomach,pancreas, ovary, head and neck, urinary bladder, premalignant skinlesions) (topical), Cytarabine (cytosine arabinoside) (acutegranulocytic and acute lymphocytic leukemias); Purine Analogs andRelated Inhibitors, such as, Mercaptopurine (6-mercaptopurine; 6-MP)(acute lymphocytic, acute granulocytic and chronic granulocyticleukemia), Thioguanine (6-thioguanine: TG) (acute granulocytic, acutelymphocytic and chronic granulocytic leukemia), Pentostatin(2′-deoxycyoformycin) (hairy cell leukemia, mycosis fungoides, chroniclymphocytic leukemia); Vinca Alkaloids, such as, Vinblastine (VLB)(Hodgkin's disease, non-Hodgkin's lymphomas, breast, testis),Vincristine (acute lymphocytic leukemia, neuroblastoma, Wilms' tumor,rhabdomyosarcoma, Hodgkin's disease, non-Hodgkin's lymphomas, small-celllung); Epipodophylotoxins, such as Etoposide (testis, small-cell lungand other lung, breast, Hodgkin's disease, non-Hodgkin's lymphomas,acute granulocytic leukemia, Kaposi's sarcoma), Teniposide (testis,small-cell lung and other lung, breast, Hodgkin's disease, non-Hodgkin'slymphomas, acute granulocytic leukemia, Kaposi's sarcoma).

(iv) Cytotoxic Agents

Representative cytotoxic agents include, but are not limited to:doxorubicin, carmustine (BCNU), lomustine (CCNU), cytarabine USP,cyclophosphamide, estramucine phosphate sodium, altretamine,hydroxyurea, ifosfamide, procarbazine, mitomycin, busulfan,cyclophosphamide, mitoxantrone, carboplatin, cisplatin, interferonalfa-2a recombinant, paclitaxel, teniposide, and streptozoci.Physicians' Desk Reference, 50th Edition, 1996.

(v) Natural Products

Representative natural products include, but are not limited to:Antibiotics, such as, Dactinomycin (actinonmycin D) (choriocarcinoma,Wilms' tumor rhabdomyosarcoma, testis, Kaposi's sarcoma), Daunorubicin(daunomycin; rubidomycin) (acute granulocytic and acute lymphocyticleukemias), Doxorubicin (soft tissue, osteogenic, and other sarcomas;Hodgkin's disease, non-Hodgkin's lymphomas, acute leukemias, breast,genitourinary thyroid, lung, stomach, neuroblastoma), Bleomycin (testis,head and neck, skin and esophagus lung, and genitourinary tract,Hodgkin's disease, non-Hodgkin's lymphomas), Plicamycin (mithramycin)(testis, malignant hypercalcema), Mitomycin (mitomycin C) (stomach,cervix, colon, breast, pancreas, bladder, head and neck); Enzymes, suchas, L-Asparaginase (acute lymphocytic leukemia); Biological ResponseModifiers, such as, Interferon-alfa (hairy cell leukemia, Kaposi'ssarcoma, melanoma, carcinoid, renal cell, ovary, bladder, non Hodgkin'slymphomas, mycosis fungoides, multiple myeloma, chronic granulocyticleukemia).

(vi) Miscellaneous Agents

Additional agents that can be used in combination or alternation withthe compounds and compositions disclosed herein include, but are notlimited to: Platinum Coordination Complexes, such as, Cisplatin(cis-DDP) Carboplatin (testis, ovary, bladder, head and neck, lung,thyroid, cervix, endometrium, neuroblastoma, osteogenic sarcoma);Anthracenedione, such as Mixtozantrone (acute granulocytic leukemia,breast); Substituted Urea, such as, Hydroxyurea (chronic granulocyticleukemia, polycythemia vera, essential thrombocytosis, malignantmelanoma); Methylhydrazine Derivatives, such as, Procarbazine(N-methylhydrazine, MIH) (Hodgkin's disease); AdrenocorticalSuppressants, such as, Mitotane (o,p′-DDD) (adrenal cortex),Aminoglutethimide (breast); Adrenorticosteriods, such as, Prednisone(acute and chronic lymphocytic leukemias, non-Hodgkin's lymphomas,Hodgkin's disease, breast); Progestins, such as, Hydroxprogesteronecaproate, Medroxyprogesterone acetate, Megestrol acetate (endometrium,breast); Stereoids, such as, include betamethasone sodium phosphate andbetamethasone acetate.

(vii) Hormones and Antagonists

Representative, nonlimiting examples of hormones and antagonistssuitable for use in combination with the compounds of the presentinvention include, but are not limited to, Estrogens: DiethylstibestrolEthinyl estradiol (breast, prostate); Antiestrogen: Tamoxifen (breast);Androgens: Testosterone propionate Fluxomyesterone (breast);Antiandrogen: Flutamide (prostate); Gonadotropin-Releasing HormoneAnalog: Leuprolide (prostate). Other hormones includemedroxyprogesterone acetate, estradiol, megestrol acetate, octreotideacetate, diethylstilbestrol diphosphate, testolactone, and goserelinacetate. Physicians' Desk Reference, 50th Edition, 1996.

B. Anti-Psoriasis Agents

The compounds of the present invention can be used in combination oralternation with agents used to treat psoriasis including, but notlimited to the following:

Topical treatments: corticosteroids (cortisone), calcipotriene (asynthetic form of vitamin D₃); coal tar; anthralin; topical retinoids(e.g. tazarotene, or Tazorac), UV light therapy.

Systemic drugs: Amevive (alefacept, LFA3TIP), Enbrel (etanercept), andRaptiva (efalizumab), Remicade (infliximab), Humira, ABX-IL8, Xanelim,psoralen, methotrexate, Tegison, Anti-CD4, Anti-IL2R (Simulect®,basiliximab), fusion proteins, HumaT4, HuMax-CD4, HuMax-IL15, IDEC-114,ISIS 2302, LFA-1 antagonists, methotrexate, MEDI-507 (siplizumab), p38kindase inhibitors, Xerecept® (hCRF), Zenapax® (anti-CD25, daclizumab),cyclosporine (Neoral™), Hydroxyurea (Hydrea™), retinoids (e.g.,acitretin (Soriatane™)) and antibiotics.

C. Anti-Inflammatory Bowel Disease (IBD) Agents

The compounds of the present invention can be used in combination oralternation with drugs or other agents used to treat IBD including, forexample, aminosalicylates, corticosteroids, antibiotics andimmunomodulators. Representative, non-limiting anti-IBD agents include:

Corticosteroids: Prednisone, Medrol®, methylprednisolone,hydrocortisone, budesonide (Entocort EC).

Aminosalicylates: sulfasalazine (Azulfidine), Rowasa, olsalazine(Dipentum®), mesalamine (Asacol,® Pentasa®), and balsalazide(Colazal,™), Balsalazide (Colazal™).

Immune System Modulators: azathioprine (Imuran), 6 mercaptopurine(Purinethol); cyclosporine A (Sandimmune®, Neoral®).

Biological therapy: Infliximab (Remicade)

Antibiotics: ciprofloxacin (Cipro, metronidazole (Flagyl), ampicillin,sulfonamide, cephalosporin, tetracycline, metronidazole, vancomycin,tobramycin.

Other agents including anti-TNF, interleukin-10 (IL-10), interferonbeta, methotrexate, zinc, tacrolimus (FK506), mycophenolate mofetil,heparin, essential fatty acids (e.g., omega-3 fatty acids (Epanova™),6-fatty acids), short chain fatty acids (SCFA) (e.g., butyrate),glutamine, phosphatidylcholine/phosphatidylinositol (PC/PI), superoxidedismutase (SOD), rosiglitazone, clotrimazole, Antegren™ (natalizumab),CNI-1493, STA-5326, Adalimumab, G-CSF, melatonin, estrogen,dehydroepiandrosterone (DHEA), vitamin A, C, E, K, carotenoids, folicacid, calcium, iron, magnesium, selenium, metallothionein, copper,fiber, probiotics (e.g., Lactobacilli, Streptococci, Bifidobacteria, ecoli), botanicals and flavinoids (e.g., ginkgo biloba, boswelliaserrata, peumus boldus, plant sterols and sterolins, bromelain,quercetin, rutin).

D. Anti-Arthritis and Osteoarthritis Agents

The compounds of the present invention can be used in combination oralternation with therapeutic agents used to treat arthritis, including,for example, nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics,biological response modifiers, corticosteroids or steroids,disease-modifying antirheumatic drugs (DMARDs), fibromyalgiamedications, osteoporosis medications, and gout medications.

NSAIDs: carboxylic acids, propionic acids, fenamates, acetic acids,pyrazolones, oxicans, alkanones, gold compounds and others that inhibitprostaglandin synthesis, preferably by selectively inhibitingcylcooxygenase-2 (COX-2). Some non-limiting examples of COX-2 inhibitorsare Celebrex (celecoxib) and Vioxx (rofacoxib). Some non-limitingexamples of NSAIDS are aspirin (acetylsalicylic acid), Dolobid(diflunisal), Disalcid (salsalate, salicylsalicylate), Trisilate(choline magnesium trisalicylate), sodium salicylate, Cuprimine(penicillamine), Tolectin (tolmetin), ibuprofen (Motrin, Advil, NuprinRufen), Naprosyn (naproxen, Anaprox, naproxen sodium), Nalfon(fenoprofen), Orudis (ketoprofen), Ansaid (flurbiprofen), Daypro(oxaprozin), meclofenamate (meclofanamic acid, Meclomen), mefenamicacid, Indocin (indomethacin), Clinoril (sulindac), tolmetin, Voltaren(diclofenac), Lodine (etodolac), ketorolac, Butazolidin(phenylbutazone), Tandearil (oxyphenbutazone), piroxicam (Feldene),Relafen (nabumetone), Myochrysine (gold sodium thiomalate), Ridaura(auranofin), Solganal (aurothioglucose), acetaminophen, colchicine,Zyloprim (allopurinol), Benemid (probenecid), Anturane (sufinpyrizone),Plaquenil (hydroxychloroquine), Aceclofenac, Acemetacin, Acetanilide,Actarit, Alclofenac, Alminoprofen, Aloxiprin, Aluminium Aspirin, AmfenacSodium, Amidopyrine, Aminopropylone, Ammonium Salicylate, Ampiroxicam,Amyl Salicylate, Anirolac, Aspirin, Auranofin, Aurothioglucose,Aurotioprol, Azapropazone, Bendazac (Bendazac Lysine), Benorylate,Benoxaprofen, Benzpiperylone, Benzydamine, Hydrochloride, BomylSalicylate, Bromfenac Sodium, Bufexamac, Bumadizone Calcium, ButibufenSodium, Capsaicin, Carbaspirin Calcium, Carprofen, Chlorthenoxazin,Choline Magnesium Trisalicylate, Choline Salicylate, Cinmetacin,Clofexamide, Clofezone, Clometacin, Clonixin, Cloracetadol, Cymene,Diacerein, Diclofenac (Diclofenac Diethylammonium Salt, DiclofenacPotassium, Diclofenac Sodium), Diethylamine Salicylate,Diethylsalicylamide, Difenpiramide, Diflunisal, Dipyrone, Droxicam,Epirizole, Etenzamide, Etersalate, Ethyl Salicylate, Etodolac,Etofenamate, Felbinac, Fenbufen, Fenclofenac, Fenoprofen Calcium,Fentiazac, Fepradinol, Feprazone, Floctafenine, Flufenamic,Flunoxaprofen, Flurbiprofen (Flurbiprofen Sodium), Fosfosal, Furprofen,Glafenine, Glucarnetacin, Glycol Salicylate, Gold Keratinate,Harpagophytum Procumbens, Ibufenac, Ibuprofen, Ibuproxam, ImidazoleSalicylate, Indomethacin (Indomethacin Sodium), Indoprofen, Isamifazone,Isonixin, Isoxicam, Kebuzone, Ketoprofen, Ketorolac Trometamol, LithiumSalicylate, Lonazolac Calcium, Lomoxicam, Loxoprofen Sodium, LysineAspirin, Magnesium Salicylate, Meclofenamae Sodium, Mefenamic Acid,Meloxicam, Methyl Butetisalicylate, Methyl Gentisate, Methyl Salicylate,Metiazinic Acid, Metifenazone, Mofebutazone, Mofezolac, MorazoneHydrochloride, Morniflumate, Morpholine Salicylate, Nabumetone, Naproxen(Naproxen Sodium), Nifenazone, Niflumic Acid, Nimesulide, Oxametacin,Oxaprozin, Oxindanac, Oxyphenbutazone, Parsalmide, Phenybutazone,Phenyramidol Hydrochloride, Picenadol Hydrochloride, PicolamineSalicylate, Piketoprofen, Pirazolac, Piroxicam, Pirprofen, Pranoprofen,Pranosal, Proglumetacin Maleate, Proquazone, Protizinic Acid,Ramifenazone, Salacetamide, Salamidacetic Acid, Salicylamide, Salix,Salol, Salsalate, Sodium Aurothiomalate, Sodium Gentisate, SodiumSalicylate, Sodium Thiosalicylate, Sulindac, Superoxide Dismutase(Orgotein, Pegorgotein, Sudismase), Suprofen, Suxibuzone, TenidapSodium, Tenoxicam, Tetrydamine, Thurfyl Salicylate, Tiaprofenic,Tiaramide Hydrochloride, Tinoridine Hydrochloride, Tolfenamic Acid,Tometin Sodium, Triethanolamine Salicylate, Ufenamate, Zaltoprofen,Zidometacin and Zomepirac Sodium.

Analgesics: acetaminophen, opioid analgesics, transdermal fentanyl

Biological response modifiers: Etanercept (Enbrel), infliximab(Remicade), adalimumab (Humira), anakinra (Kineret)

Corticosteroids: glucocorticoids (GC), Aerobid (Aerobid-M, flunisolide),Azmacort (triamcinolone acetonide), Beclovet (Vanceril, beclomethasonedipropionate), Flovent (fluticasone), Pulmicort (budesonide),prednisolone, hydrocortisone, adrenaline, Alclometasone Dipropionate,Aldosterone, Amcinonide, Beclomethasone Dipropionate, Bendacort,Betamethasone (Betamethasone Acetate, Betamethasone Benzoate,Betamethasone Dipropionate, Betamethasone Sodium Phosphate,Betamethasone Valerate), Budesonide, Ciclomethasone, Ciprocinonide,Clobetasol Propionate, Clobetasone Butyrate, Clocortolone Pivalate,Cloprednol, Cortisone Acetate, Cortivazol, Deflazacort, DeoxycortoneAcetate (Deoxycortone Pivalate), Deprodone, Desonide, Desoxymethasone,Dexamethasone (Dexamethasone Acetate, Dexamethasone Isonicotinate,Dexamethasone Phosphate, Dexamethasone Sodium Metasulphobenzoate,Dexamethasone Sodium Phosphate), Dichlorisone Acetate, DiflorasoneDiacetate, Diflucortolone Valerate, Difluprednate, Domoprednate,Endrysone, Fluazacort, Fluclorolone Acetonide, Fludrocortisone Acetate,Flumethasone (Flumethasone Pivalate), Flunisolide, FluocinoloneAcetonide, Fluocinonide, Fluocortin Butyl, Fluocortolone (FluocortoloneHexanoate, Fluocortolone Pivalate), Fluorometholone (FluorometholoneAcetate), Fluprednidene Acetate, Fluprednisolone, Flurandrenolone,Fluticasone Propionate, Formocortal, Halcinonide, HalobetasolPropionate, Halometasone, Hydrocortamate Hydrochloride, Hydrocortisone(Hydrocortisone Acetate, Hydrocortisone Butyrate, HydrocortisoneCypionate, Hydrocortisone Hemisuccinate, Hydrocortisone SodiumPhosphate, Hydrocortisone Sodium Succinate, Hydrocortisone Valerate),Medrysone, Meprednisone, Methylprednisolone (Methylprednisolone Acetate,Methylprednisolone, Hemisuccinate, Methylprednisolone Sodium Succinate),Mometasone Furoate, Paramethasone Acetate, Prednicarbate, PrednisolamateHydrochloride, Prednisolone (Prednisolone Acetate, PrednisoloneHemisuccinate, Prednisolone Hexanoate, Prednisolone Pivalate,Prednisolone Sodium Metasulphobenzoate, Prednisolone Sodium Phosphate,Prednisolone Sodium Succinate, Prednisolone Steaglate, PrednisoloneTebutate), Prednisone (Prednisone Acetate), Prednylidene, Procinonide,Rimexolone, Suprarenal Cortex

DMARDs: hydroxychloroquine (Plaquenil), cyclosphosphamide (Cytoxan),chlorambucil (Leukeran), the gold compound auranofin (Ridaura),sulfasalazine (Azulfidine) and minocycline (Dynacin, Minocin),cyclosporine (Sandimmune, Neoral), toll-like receptor agonists andantagonists. Other forms of DMARDs include immuno suppressants and tumornecrosis factor (TNF) blockers. Representative, non-limiting TNFblockers include etanercept (Enbrel), infliximab (Remicade) andadalimumab (Humira).

Another anti-rheumatic drug suitable for use in combination with thecompound of the present invention is an Interleukin-1 receptorantagonist (IL-1Ra).

Fibromyalgia medications: amitriptyline (Elavil, Endep) and fluoxetine(Prozac); cylobenzaprine (Cycloflex, Flexeril), tramadol (Ultram),gabapentin (Neurontin), and dual-reputake inhibitors.

Osteoperosis medications: estrogens, parathyroid hormones (calcitonin)bisphosphonates (alendronate and risedronate sodium), selective receptormolecules (raloxifene hydrochloride) and bone formation agents(teriparatide).

Gout medications: allopurinol (Lopurin, Zyloprim), probenecid (Benemid,Probalan), losartan (Cozaar, Hyzaar), fenofibrate (Tricor).

Agents used to treat osteoarthritis, including but not limited to:

Analgesics (e.g., acetaminophen), Paracetamol, dextropropoxyphene,non-steroidal anti-inflammatory drug (NSAID) (e.g., Advil, Motrin IB,Aleve, ketoprofen, Ibuprofen and naproxen, aspirin), corticosteroids,Doxycycline, Kineret, MMP inhibitors, Hydroxychloroquine (Plaquenil)glucosamine, chondroitin, COX-2 inhibitors (e.g., Vioxx® (rofecoxib),Celebrex® (celecoxib), Bextra® (valdecoxib), hyaluronans, Hyalgan®(hyaluronan), Synvisc® (hylan G-F20), topical treatments (non-steroidalanti-inflammatory drugs, capsaicin).

E. Anti-Chronic Obstructive Pulmonary Disease Agents

The compounds of the present invention can be used in combination oralternation with therapeutic agents used to treat chronic obstructivepulmonary disease, including, but not limited to:

Bronchiodilator therapy: B2 adrenoreceptor agonists (e.g., salbutamol(Ventolin®, Ventodisk®) and terbutaline sulphate (Bricanyl), fenoterolhydrobromide (Berotec®), rimiterol hydrobromide (Pulmadil®), pirbuterol(Exirel®), reproterol hydrochloride (Bronchodil®) and tulobuterolhydrochloride (Brelomax®)), anticholinergic agents (Ipratropium bromide,Atrovent®, and Oxitropium bromide, Oxivent®, (Tiotropium bromide, Ba 679BR).

Methylxanthines including theophylline (Theo-dur®, Phyllocontin®,Uniphyllin®).

Corticosteriods including beclomethasone dipropionate (Becotide®,Becloforte®) and budesonide (Pulmicort®), flunisolide inhalation,triamcinolone inhalation, fluficasone inhalation, beclomethasoneinhalation, Prednisone, methylprednisolone.

Other agents include, for example, Combivent (ipratropium/salbutamol),Advair/Seretide (flucatisone/salmeterol), Symbicort(formoterol/budesonide), Asmanex (mometasone furoate), Foradil, Ariflo(cilomilast), ONO 6126, talnetant, 842470/AWD 12281, IC 485, CP 671305.

F. Anti-Asmtha Agents

The compounds of the present invention can be used in combination oralternation with therapeutic agents used to treat asmtha, including, forexample:

Anti-allergics: cromolyn sodium (Intal, Lomudal, Nasalcrom,Novo-Cromolyn, Rynacrom, ketotifen fumarate (ketotifen fumarate).

Anti-inflammatories: including both non-steroidal and steroidal.Non-steroidal anti-inflammatories include, e.g., nedocromil (Tilade).Steroidal anti-inflammatories include, e.g., beclomethasone dipropionate(Aerobec, Beclovent, Beclodisk, Becloforte, Becodisk), budesonide(Pulmicort, Rhinocort), dexamethasone sodium phosophate (Decadronphosphate), flunisolide (Aerobid, Bronalide, Nasalide), fluticasonepropionate, triamcinolone acetonide (Azmacort, Nasacort).

Anticholinergics: ipratropium bromide (Atrovent) belladonna alkaloids,Atrovent (ipratropium bromide), atropine, and oxitropium bromide.

Antihistimines: alkylamines, ethanolamines ethylenediamines,piperazines, piperidines or phenothiazines; Chlortrinmeton (Teldrin,chlorpheniramine), Atrohist (brompheniramine, Bromarest, Bromfed,Dimetane), Actidil (triprolidine), Dexchlor (Poladex, Polaramine,dexchlorpheniramine), Benadryl (diphen-hydramine), Tavist (clemastine),Dimetabs (dimenhydrinate, Dramamine, Mainline), PBZ (tripelennamine),pyrilamine, Marezine (cyclizine), Zyrtec (cetirizine), hydroxyzine,Antivert (meclizine, Bonine), Allegra (fexofenadine), Hismanal(astemizole), Claritin (loratadine), Seldane (terfenadine), Periactin(cyproheptadine), Nolamine (phenindamine, Nolahist), Phenameth(promethazine, Phenergan), Tacaryl (methdilazine) and Temaril(trimeprazine).

β₂-adrenergic agonists (beta agonists): albuterol (salbutamol,Proventil, Ventolin), terbutaline, Maxair (pirbuterol), Serevent(salmeterol), epinephrine, metaproterenol (Alupent, Metaprel), Brethine(Brie anyl, Brethaire, terbutaline sulfate), Tornalate (bitolterol),isoprenaline, ipratropium bromide, bambuterol hydrochloride, bitolterolmeslyate, broxaterol, carbuterol hydrochloride, clenbuterolhydrochloride, clorprenaline hydrochloride, efirmoterol fumarate,ephedra (source of alkaloids), ephedrine (ephedrine hydrochloride,ephedrine sulfate), etafedrine hydrochloride, ethylnoradrenalinehydrochloride, fenoterol hydrochloride, hexoprenaline hydrochloride,isoetharine hydrochloride, isoprenaline, mabuterol, methoxyphenaminehydrochloride, methylephedrine hydrochloride, orciprenaline sulphate,phenylephrine acid tartrate, phenylpropanolamine (phenylpropanolaminepolistirex, phenylpropanolamine sulphate), pirbuterol acetate,procaterol hydrochloride, protokylol hydrochloride, psuedoephedrine(psuedoephedrine polixtirex, psuedoephedrine tannate, psuedoephedrinehydrochloride, psuedoephedrine sulphate), reproterol hydrochloride,rimiterol hydrobromide, ritodrine hydrochloride, salmeterol xinafoate,terbutaline sulphate, tretoquinol hydrate and tulobuterol hydrochloride.

Leukotriene Receptor Antagonists: zafirlukast (Accolate); zileutonmontelukast (Zyflo, Singulair).

Xanthines (bronchodilators): theophylline (e.g., Aerolate, Respbid,Slo-bid), dyphylline, oxtriphylline.

Combination medications: Advair (salmeterol, fluticasone), Aerocrom(cromolyn sodium, albuterol), Asbron G (theophylline sodium glycinate,guaifenesin (expectorant), Berodual (ipratropium HBr, fenoterol HBr),Bronkaid Caplets (ephedrine sulfate, guaifenesin), Combivent (salbutamol(albuterol), ipratropium bromide), Congess (guaifenesin,pseudoephedrine), Duo-Medihaler (isoproterenol hydrochloride,phenylephrine bitartrate), Duovent (fenoterol hydrobromide, ipratropiumbromide), Marax (ephedrine sulfate, theophylline, Atarax (hydroxyzineHCl)), Primatene Tablets (theophylline, ephedrine HCl), Quadrinal(theophylline calcium salicylate, ephedrine HCl, phenobarbital,potassium iodide), Rynatuss (carbetapentane tannate, chlorpheniraminetannate, ephedrine tannate, phenylephrine tannate), Tedral(theophylline, ephedrine HCl, Phenobarbital), Ventolin-Plus (albuterol,beclomethasone, dipropionate).

Other anti-asthma agents suitable for use in combination or alternationwith the antifolates of the present invention include xanthines andmethylxanthines, such as Theo-24 (theophylline, Slo-Phylline,Uniphyllin, Slobid, Theo-Dur), Choledyl (oxitriphylline), aminophylline;phosphodiesterase inhibitors such as zardaverine; calcium antagonistssuch as nifedipine; and potassium activators such as cromakalim.

In one embodiment, the compound is administered in combination oralterantion with one or more prophylactic agent(s). Examples ofprophylactic agents that can be used in alternation or combinationtherapy include but are not limited to sodium cromoglyc ate, Intal(cromolyn sodium, Nasalcrom, Opticrom, Crolom, Ophthalmic Crolom),Tilade (nedocromil, nedocromil sodium) and ketotifen.

G. Anti-Multiple Sclerosis Agents

The antifolates of the present invention can be used in combination oralternation with agents used to treat multiple sclerosis, including forexample: ReVia (Naltrexone), Pregabalin, Copaxone® (Glatiramer acetate),Provigil (Modafinil), Symmetrel (Amantadine), Rebif® (Interferonbeta-1a), solu-Medrol (I.V. Methylprednisolone), Avonex® (Interferonbeta-1a), Betaseron® (Interferon beta-1b). Other representativeanti-multiple sclerosis agents for use in combination with the compoundsof the present invention include:

Chemotherapetuic agents: Mitoxantrone (Novantrone), Azathioprine(Imuran), Cyclophosphamide (Cytoxan, Neosar), Cyclosporine (Sandimmune),methotrexate, Cladribine.

Corticosteroids and ACTH: MethylPrednisolone (Depo-Medrol), Prednisone(Deltasone), Prednisolone (Delta-Cortef), Dexamethasone (Medrol,Decadron), Adreno-corticotrophic Hormone (ACTH) and Corticotropin(Acthar).

Dysaesthesia agents: Carbamazepine (Tegretol, Epitol, Atretol,Carbatrol), Gabapentin (Neurotonin), Topiramate (Topamax), Zonisamide(Zonegran), Phenytoin (Dilantin), Amitriptyline (Elavil), Imipramine,Imipramine, Doxepin (Sinequan, Adapin, Triadapin, Zonalon),Protriptyline (Vivactil), Pentoxifylline (Trental), Ibprofen (Neurofen),aspirin, acetaminophen, Hydroxyzine.

Agents used to treat depression and insomnia: Fluoxetine (Prozac),Sertraline (Zoloft), Venlafaxine, Citalopram (Celexa), Parocetine(Paxil, Seroxat), Trazodone (Desyrel, Trialodine), Nortriptyline,Imipramine, Dothiepin, Lofepramine. Tranylcypromine, Moclobemide,Nefazodone, Mirtazapine, diazepam (Valium), alprazolam, Buspirone.

Agents used to treat fatigue: for example, amantadine (Symmetrel),pemoline (Cylert), and Modafinil.

Agents used to treat spasticity and muscle tics: Diazepam, Clonazepam,Baclofen, Dantrolene sodium, Dantrolene sodium, Clonidine, and BotulinumToxin.

Agents used to treat tremors: Clonazepam, Gabapentin, Primidone,Botulinum toxin, Acetazolamide, Levodopashy, carbidopa, and Isoniazid.

Agents used to treat nausea and dizziness: Meclizine, Dimenhydrinate,Prochlorperazine, Scopolamine, and Diphenhydramine.

Antivirals and vaccinations: flu jabs and acyclovir.

Agents used to treat urinary problems: Oxybutynin, Desmopressin,Vasopressin, Tolterodine, carbamazepine, Imipramine, Bethane,Phenoxybenzamine, Terazosin, Propantheline, Oxybutynin, Hyoscyamine,Hyoscyamine, Diazepam, Methenamine, Nitrofurantoin, Phenazopyridine,Ciprofloxacin. Also agents used to treat bowel problems including, forexample, Bisacodyl and Psyllium hydrophilic mucilloid

Other agents and therapies include, for example, potassium channelblockers (e.g., 4-aminopyridine (4-AP and Fampridine), 3,4Diaminopyridine, alpha-interferon, Alemtuzumab, anti-T-cell monoclonalantibodies, anti-lymphocyte globulin, IV Immunoglobin, Eliprodil, oralmyelin (Myloral), cladribine (Leustatin, 2-CDA), cyclophosphamide(Cytoxan), Natalizumab, gamma-interferon, IL-2-toxin, mitoxantrone,gabapentin, and methylprednisolone, methotrexate, Pregabalin, Procarin(transdermal histamine), plasmapheresis (plasma exchange), PUVA(psoralen ultraviolet light), t-cell receptor therapy, t-cellvaccination, total lymphoid irradiation, transforming growth factor-beta(TGF), tumor necrosis factor antagonists, and Ziconotide.

The present invention is described by way of illustration, in thefollowing examples. It will be understood that one of ordinary skill inthat art that these examples are in no way limiting and that variationof detail can be made without departing from the spirit and scope of theinvention.

EXAMPLES Example 1 Inhibition of Dihydrofolate Reductase and ThymidylateSynthase

The ability of M-TREX to inhibit recombinant dihydrofolate reductase(DR) and thymidylate synthase (TS) in vitro studied in comparison toother antifolate drugs. The results are summarized in Table I:

Compound I₅₀ (human DHFR) I₅₀ (Human TS) MTX 1.7 × 10⁻⁸M — TOMUDEX — 1.0× 10⁻⁶M MDAM 4.4 × 10⁻⁸M — MTA (LY-231514) 6.6 × 10⁻⁶M 1.1 × 10⁻³MM-TREX 1.7 × 10⁻⁸M 3.8 × 10⁻⁶M

These results establish that M-TREX is a potent inhibitor of both DHFRand TS.

Example 2 Formulation of MTREX in a Microcrystalline Cellulose CapsuleMaterials

Avicel PH 101 will be used to dilute the drug to the required dosestrengths prior to capsule filling. Additional materials are listed inTable 1.

TABLE 1 Material Grade Function Supplier Avicel PH101 EP Filler/HONEYWILL & (Microcrystalline Cellulose) Diluent STEIN White HardGelatin EP Shell CAPSUGEL Capsules Size 0

A Semi-automated capsule filler, such as a Feton Plate and a blender,such as a Turbula—Drum will be used to formulate the drug.

Methods

LOD—Loss On Drying

The LOD will be measured using Sartorius MA45 infra-red balance. Theprogram selected for the analysis will be dependant on the physicalproperties of the drug. An appropriate sample size will be weighed outonto the aluminum tray of the LOD balance. Care will be taken to ensurethat sample is leveled and in the middle of the tray, with no gaps.Using the appropriate method, the loss on drying analysis will beperformed. The LOD value will be recorded in percentage.

Carr's Compressibility Index—Bulk/Tap Density

The sample will be added to a measuring cylinder to an appropriatevolume. The weight and the volume of the sample will be recorded asW_(p), poured weight and V_(p), poured volume respectively. The cylinderwill be place upon the jolting volumeter and oscillated for appropriatenumber of taps. The final volume of the sample will be recorded asV_(t), tapped volume. The following calculations will be performed asper equations 1-3.

Poured Density (P _(p))=(W_(p)/V_(p))   EQUATION 1

Tapped Density (P _(t))=(W_(p)/V_(t))   EQUATION 2

Carrs Compressibility Index (CCI)=[(P _(r) −P _(p))/P _(t)]×100  EQUATION 3

Semi-Automated Capsule Filling Method

Probe formulations including placebo (Avicel PH101 only) detailed inTable 3, will be manufactured using a Turbula drum blender set to anappropriate mixing duration. Each formulation will undergo anencapsulation process feasibility study using semi-automated capsulefiller—Feton plate. The content uniformity data, of the powder blend andthe filled capsules will be determined.

Capsules will be prepared at the highest and lowest dosage strengths andthese will be placed on accelerated stability. Additional powder blendscharacterization such as LOD and Carr's index, detailed will also beperformed.

TABLE 3 Materials Function mg/Capsule mg/Capsule mg/Capsule MTREX Drug1.0 2.5 5 Avicel PH101 Filler/ — — — (Microcrystalline DiluentCellulose)

Accelerated Stability Study

An accelerated stability study as outlined in Table 4, will beperformed. Samples of the formulated drug will be placed at 25 C/60% RHand 40° C/75% RH for up to 8 weeks. Appearance, assay and degradationtesting for active drug MTREX will be performed at initial, 4 and 8 weektime-points. Note, all analysis will be performed by QuintilesAnalytical Development group. Details of these methods will be coveredby separate documents from this group.

TABLE 4 Outline of Stress Stability Program Time- points/(weeks) 0 4 8Conditions  5° C. T S S 25° C./60% RH n/a T T 40° C./75% RH n/a T TT—denotes test for Appearance, Assay and Degradation S—Storage only willbe tested if 25° C./60% RH fails.

All of the compositions, methods, and/or processes disclosed and claimedherein can be made and executed without undue experimentation in lightof the present disclosure. While the compositions and methods of thisinvention have been described in terms of preferred embodiments, it willbe apparent to those of skill in the art that variations may be appliedto the compositions, methods and/or processes and in the steps or in thesequence of steps of the methods described herein without departing fromthe concept and scope of the invention. More specifically, it will beapparent that certain agents which are both chemically andphysiologically related may be substituted for the agents describedherein while the same or similar results would be achieved. All suchsimilar substitutes and modifications apparent to those skilled in theart are deemed to be within the scope and concept of the invention.

1. A method for treating a condition responsive to inhibition of one ormore of dihydrofolate reductase (DHFR), thymidylate synthase (TS),folylpolyglutamyl synthase (FPGS), glycinamide ribonucleotidetransformylase (GAR), and aminoimidazole carboxamide ribonucleotidetransformylase (AICAR), the method comprising administering to a patientin need of treatment for the condition an effective amount ofmethotrexate and a compound of formula (I):

or its pharmaceutically acceptable salt, wherein: X is CH₂, CHCH₃,CH(CH₂CH₃), NH, NCH₃, or NR⁷; R¹, R², R³, R⁴, and R⁷ are independentlyselected from H, optionally substituted alkyl, optionally substitutedalkenyl or alkynyl, acyl, —C(O)-(alkyl), —C(O)-(alkenyl),—C(O)-(alkynyl), —C(═Y³)V³, lipid, phospholipid, carbohydrate, peptide,cholesterol, an amino acid residue, an amino acid acyl residue, or otherpharmaceutically acceptable leaving group that is capable of providing afree amine when administered in vivo; R⁵ and R⁶ are independentlyselected from H, optionally substituted alkyl, optionally substitutedalkenyl or alkynyl, lipid, phospholipid, carbohydrate, peptide,cholesterol, an amino acid residue, or other pharmaceutically acceptableleaving group that is capable of providing a —C(═Y)V⁻ or —C(═Y)VH moietywhen administered in vivo; each Y¹, Y², and Y³ independently is O, S, orNJ¹; each V¹ and V² independently is O, S, or NJ¹; each V³ independentlyis OH, OJ¹, SH, SJ¹, NH₂, NHJ¹, NJ¹J², CH₃, CH₂R¹⁰¹, CHR¹⁰¹R¹⁰², orCR¹⁰¹R¹⁰²R¹⁰³; each J¹ and J² independently are hydrogen, alkyl,alkenyl, alkynyl, alkaryl, cycloalkyl, aryl, heteroalkyl, heterocycle,heteroaryl, hydroxyl, alkoxy, or amine; and each R¹⁰¹, R¹⁰², and R¹⁰³are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl,heteroaryl, heteroalkyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro,SO₂, SO₃, thioalkyl, or amino.
 2. The method of claim 1, wherein thecompound of formula (I) and the methotrexate are administeredseparately.
 3. The method of claim 1, wherein the compound of formula(I) and the methotrexate are administered in an effective ratio ofdosages.
 4. The method of claim 1, wherein the condition is a conditionof abnormal cellular proliferation, inflammation, or both abnormalcellular proliferation and inflammation.
 5. The method of claim 1,wherein the condition is selected from the group consisting ofpsoriasis, psoriatic arthritis, atherosclerosis, inflammatory boweldisease (IBD), chronic obstructive pulmonary disease (COPD),sarcoidosis, asthma, arthritis, osteoarthritis, cardiovascular disease,multiple sclerosis, Parkinson's disease, Alzheimer's disease, Crohn'sdisease, ulcerative colitis, rheumatoid arthritis, and systemic lupuserythematosus.
 6. The method of claim 5, wherein the condition isrheumatoid arthritis.
 7. The method of claim 1, wherein the compound offormula (I) is in the form of a pharmaceutically acceptable salt.
 8. Themethod of claim 7, wherein the salt is an alkali metal salt.
 9. Themethod of claim 8, wherein the alkali metal is sodium or potassium. 10.The method of claim 1, wherein Y¹, Y², V¹, and V² are O.
 11. The methodof claim 1, wherein R¹, R², R³, and R⁴ are H.
 12. The method of claim 1,wherein X is CH₂.
 13. The method of claim 1, wherein R⁵ and R⁶ areindependently a pharmaceutically acceptable leaving group that iscapable of providing a —C(═Y)V⁻ moiety when administered in vivo. 14.The method of claim 1, wherein the compound of formula (I) is thecompound of the following structure:

or its pharmaceutically acceptable salt.
 15. The method of claim 14,wherein the compound is in the form of a pharmaceutically acceptablesalt.
 16. The method of claim 15, wherein the salt is an alkali metalsalt.
 17. The method of claim 16, wherein the alkali metal is sodium orpotassium.
 18. A pharmaceutical composition comprising apharmaceutically acceptable carrier, methotrexate, and a compoundaccording to formula (I):

or its pharmaceutically acceptable salt, wherein: X is CH₂, CHCH₃,CH(CH₂CH₃), NH, NCH₃, or NR⁷; R¹, R², R³, R⁴, and R⁷ are independentlyselected from H, optionally substituted alkyl, optionally substitutedalkenyl or alkynyl, acyl, —C(O)-(alkyl), —C(O)-(alkenyl),—C(O)-(alkynyl), —C(═Y³)V³, lipid, phospholipid, carbohydrate, peptide,cholesterol, an amino acid residue, an amino acid acyl residue, or otherpharmaceutically acceptable leaving group that is capable of providing afree amine when administered in vivo; R⁵ and R⁶ are independentlyselected from H, optionally substituted alkyl, optionally substitutedalkenyl or alkynyl, lipid, phospholipid, carbohydrate, peptide,cholesterol, an amino acid residue, or other pharmaceutically acceptableleaving group that is capable of providing a —C(═Y)V⁻ or —C(═Y)VH moietywhen administered in vivo; each Y¹, Y², and Y³ independently is O, S, orNJ¹; each V¹ and V² independently is O, S, or NJ¹; each V³ independentlyis OH, OJ¹, SH, SJ¹, NH₂, NHJ¹, NJ¹J², CH₃, CH₂R¹⁰¹, CHR¹⁰¹R¹⁰², orCR¹⁰¹R¹⁰²R¹⁰³; each J¹ and J² independently are hydrogen, alkyl,alkenyl, alkynyl, alkaryl, cycloalkyl, aryl, heteroalkyl, heterocycle,heteroaryl, hydroxyl, alkoxy, or amine; and each R¹⁰¹, R¹⁰², and R¹⁰³are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl,heteroaryl, heteroalkyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro,SO₂, SO₃, thioalkyl, or amino.
 19. The pharmaceutical composition ofclaim 18, wherein the compound of formula (I) is in the form of apharmaceutically acceptable salt.
 20. The pharmaceutical composition ofclaim 18, wherein Y¹, Y², V¹, and V² are O.
 21. The pharmaceuticalcomposition of claim 18, wherein R¹, R², R³, and R⁴ are H.
 22. Thepharmaceutical composition of claim 18, wherein X is CH₂.
 23. Thepharmaceutical composition of claim 18, wherein R⁵ and R⁶ areindependently a pharmaceutically acceptable leaving group that iscapable of providing a —C(═Y)V⁻ moiety when administered in vivo. 24.The pharmaceutical composition of claim 18, wherein the compound offormula (I) is the compound of the following structure:

or its pharmaceutically acceptable salt.
 25. The pharmaceuticalcomposition of claim 24, wherein the compound is in the form of thepharmaceutically acceptable salt.
 26. The pharmaceutical composition ofclaim 25, wherein the salt is an alkali metal salt.
 27. Thepharmaceutical composition of claim 26, wherein the alkali metal issodium or potassium.